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PROCEDURES IN COSMETIC DERMATOLOGY
SERIES
THIRD EDITION

Chemical
Peels
Editor
Suzan Obagi, MD
Associate Professor of Dermatology
Associate Professor of Plastic Surgery
Director
UPMC Cosmetic Surgery & Skin Health Center
Sewickley, PA, USA
Series Editor
Jeffrey S. Dover, MD, FRCPC
Associate Professor of Clinical Dermatology, Yale University School of Medicine
Adjunct Professor of Medicine (Dermatology), Dartmouth Medical School
Director, SkinCare Physicians of Chestnut Hill, Chestnut Hill, MA, USA
Associate Editor
Murad Alam, MD, MSCI
Associate Professor of Dermatology, Otolaryngology, and Surgery
Chief, Section of Cutaneous and Aesthetic Surgery, Northwestern University, Chicago, IL, USA
Elsevier
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St. Louis, Missouri 63043

PROCEDURES IN COSMETIC DERMATOLOGY SERIES:

CHEMICAL PEELS, THIRD EDITION ISBN: 978-0-323-65389-3
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 CONTRIBUTORS

Richard Hector Bensimon, MD Joe Niamtu III, DMD

Medical Director Private Practice
Plastic Surgery Cosmetic Facial Surgery
Bensimon Center, Richmond, VA, USA
Portland, OR, USA
Suzan Obagi, MD
Claudia Borelli, MD Associate Professor of Dermatology,
Associate Professor of Dermatology Associate Professor of Plastic Surgery,
Director, Aesthetic Dermatology and Laser Unit Director
­Department of Dermatology Eberhard-Karls-­ UPMC Cosmetic Surgery & Skin Health Center,
University Tuebingen Sewickley, PA, USA
President of German Aesthetic Dermatology and
Cosmetology Working group ADK Past President Jeave Reserva, MD
International Peeling Society IPS Dermatology Resident
Tuebingen, Germany Division of Dermatology
Loyola University Medical Center,
Desmer Destang, DDS, MSc (Ortho), MSc (Derm), Maywood, IL, USA
MSc (Aesth Med)
Medical Director, Dermalogics Aesthetic Dermatology, Barry Resnik, MD
St. Lucia Private Practice
Lecturer in Cosmetic Medicine, University of South Resnik Skin Institute Miami
Wales, Cardiff, UK Voluntary Clinical Professor
Dr Phillip Frost Department of Dermatology and
Luc Dewandre, MD ­Cutaneous Surgery
Consultant, Internal Medical Service, Paris, France University of Miami Miller School of Medicine,
Consultant in Aesthetic Medicine, Vitality Institute, Miami, FL, USA
Miami, FL, USA
Peter Rullan, MD
Sabrina Fischer, MD Medical Director
Associate Professor of Dermatology Dermatology Institute
Aesthetic Dermatology and Laser Unit Department of Volunteer Clinical Faculty
Dermatology Eberhard-Karls-University University of California San Diego,
Tuebingen San Diego, CA, USA
Tuebingen, Germany
Jaishree Sharad, MBBS, DDV, MD
Marina Landau, MD Cosmetic Dermatologist
Senior Dermatologist Medical Director
Dermatology Skinfiniti Aesthetic Skin and Laser Clinic,
Wolfson Medical Center, Mumbai, India
Holon, Israel

iii
iv CONTRIBUTORS

David Surprenant, MD Rebecca Tung, MD

Dermatology Resident Mohs and Dermatologic Surgeon
Division of Dermatology Florida Dermatology and Skin Cancer Centers,
Loyola University Medical Center, Winter Haven, FL, USA
Maywood, IL, USA
Carlos G. Wambier, MD, PhD
Alain Tenenbaum, MD, PhD, DSc Assistant Professor of Dermatology, Clinician Educator
Swiss National Delegate Department of Dermatology, The Warren Alpert Medical
EAFPS, School of Brown University
Lübeck, Germany, President Providence, RI, USA
SACDAM,
Engelberg, Switzerland, Vice President Carolyn Willis, MD
IPSC, Dermatology
Alpnach Dorf, Switzerland, Researcher University of Pittsburgh Medical Center,
Research and Development Sewickley, PA, USA
Styling Cosmetics AG,
Engelberg, Switzerland

Yardy Tse, MD
Assistant Clinical Professor,
Department of Medicine/Dermatology,
University of California, San Diego; SkinCare
Physicians and Surgeons Inc., Encinitas, CA, USA
 S E R I E S P R E FAC E , F I R S T E D I T I O N
While dermatologists have been procedurally inclined
since the beginning of the specialty, particularly rapid
change has occurred in the past quarter century. The
advent of frozen section technique and the golden age
of Mohs skin cancer surgery has led to the formal incor-
poration of surgery within the dermatology curriculum.
More recently, technological breakthroughs in mini-
mally invasive procedural dermatology have offered an
aging population new options for improving the appear-
ance of damaged skin.
Procedures for rejuvenating the skin and adjacent
regions are actively sought by our patients. Significantly,
dermatologists have pioneered devices, technologies, and
medications that have continued to evolve at a startling
pace. Numerous major advances, including virtually all
cutaneous lasers and light-source based procedures, botu-
linum exotoxin, soft tissue augmentation, dilute anesthesia
liposuction, leg vein treatments, chemical peels, and hair
transplants, have been invented or developed and enhanced
by dermatologists. Dermatologists understand procedures,
and we have special insight into the structure, function, and
workings of skin. Cosmetic dermatologists have made reju-
venation accessible to risk-averse patients by emphasizing
safety and reducing operative trauma. No specialty is better
positioned than dermatology to lead the field of cutaneous
surgery while meeting patient needs.
As dermatology grows as a specialty, an ever-increas-
ing proportion of dermatologists will become proficient
in the delivery of different procedures. Not all dermatol-
ogists will perform all procedures, and some will perform
very few, but even the less procedurally directed among
us must be well-versed in the details to be able to guide
and educate our patients. Whether you are a skilled der-
matologic surgeon interested in further expanding your
surgical repertoire, a complete surgical novice wish-
ing to learn a few simple procedures, or somewhere in
between, this book and this series are for you.
The volume you are holding is one of a series enti-
tled Procedures in Cosmetic Dermatology. The purpose
of each book is to serve as a practical primer on a major
topic area in procedural dermatology.
If you want to make sure you find the right book for
your needs, you may wish to know what this book is and
what it is not. It is not a comprehensive text grounded
in theoretical underpinnings. It is not exhaustively ref-
erenced. It is not designed to be a completely unbiased
review of the world’s literature on the subject. At the
same time, it is not an overview of cosmetic procedures
that describes these in generalities without providing
enough specific information to actually permit someone
to perform the procedures. And importantly, it is not so
heavy that it can serve as a doorstop or shelf filler.
What this book and this series offer is a step-by-
step, practical guide to performing cutaneous surgical
procedures. Each volume in the series has been edited
by a known authority in that subfield. Each editor has
recruited other equally practical-minded, technically
skilled, hands-on clinicians to write the constituent
chapters. Most chapters have two authors to ensure that
different approaches and a broad range of opinions are
incorporated. On the other hand, the two authors and
the editors also collectively provide a consistency of tone.
A uniform template has been used within each chapter
so that the reader will be easily able to navigate all the
books in the series. Within every chapter the authors
succinctly tell it like they do it. The emphasis is on thera-
peutic technique; treatment methods are discussed with
an eye to appropriate indications, adverse events, and
unusual cases. Finally, this book is short and can be read
in its entirety on a long plane ride. We believe that brev-
ity paradoxically results in greater information transfer
because cover-to-cover mastery is practicable.
Most of the books in the series are accompanied by
videos that demonstrate the procedures discussed in that
text. Some of you will turn immediately to the video and
use the text as a backup to clarify complex points, whereas
others will prefer to read first and then view the video to
see the steps in action. Choose what suits you best.
We hope you enjoy this book and the rest of the
books in the series and that you benefit from the many
hours of clinical wisdom that have been distilled to pro-
duce it. Please keep it nearby where you can reach for it
when you need it.
Jeffrey S. Dover, MD, FRCPC,
Murad Alam, MD, MSCI
v
S E R I E S P R E FA C E , T H I R D E D I T I O N
As this Procedures in Cosmetic Dermatology series
undergoes another iteration, it is clear our mission
that was initiated 15 years ago to provide succinct and
current expert guidance regarding particular cosmetic
procedures remains highly relevant. Our portable, travel-
ready format continues to match the ever-shortening
attention span of the overwhelmed physician. Indeed,
similar series of slim volumes have emerged in this and
other procedural specialties—versions of the sincerest
form of flattery.
Even so, changes need to be made. As the evolution
and exponential growth of cosmetic dermatology con-
tinues, new procedures are created, and multiple vari-
ants of existing drugs, devices, and techniques emerge.
The volumes in the series have been updated to reflect
these advances so that the books are now better but
remain concise and highly practical.
We are also cognizant of the decline of paper pub-
lishing. To preserve the environment and provide
content everywhere, all the time, and on all types
of media, the series will be available in whole and
vi
chapter-by-chapter in various electronic formats and
on several platforms. We have expanded the video
offerings because they are worth many pages of text
and are easier to follow.
As always, we are very grateful to our chapter book
editors and authors. These practitioners are among
the most prominent, bright, erudite, and skilled in the
world. They have worked tirelessly to provide a uniform
tone and structure. It is our hope that you find that these
multiauthored books read like a single person wrote
them, whose writing is a paragon of clarity.
Our thanks are also due to Elsevier, our publisher
since the start. Elsevier has provided our rapid publish-
ing window, which allows content to be put out and dis-
seminated before it goes out of date.
Finally, thanks to you, the reader, for continuing to
use these texts. We wish you the joy of learning some-
thing new and then delighting your patients with your
freshly honed skills.
Jeffrey S. Dover, MD, FRCPC
Murad Alam, MD, MSCI
 CHEMICAL PEELS, THIRD EDITION
It is with much excitement that I bring to you the third
edition of Chemical Peels! This latest textbook on peels
will take your knowledge to the next level, building on
what was covered in previous editions. Chemical peels
will be covered by experts recognized worldwide for
their innovation, talent, and skills. This international
group of thought leaders will cover the entire approach
to the skin resurfacing patient from evaluation, to skin
preparation, to performing peels ranging from light
peels to the advanced deep peels, and finally to recog-
nizing and managing complications. The new edition
features many new chapters dedicated to an in-depth
dive into a specific peel or skin condition. These new
chapters include trichloroacetic acid (TCA) peels of
the chest, neck, and upper extremities; peels as an adju-
vant treatment of acne; chemical peels in male patients;
several chapters on unique approaches to acne scars; a
chapter on combining peels with surgical procedures;
and several chapters that illustrate safely performing
deeper, modified phenol peels with wonderful photo-
graphs to accompany the text. Videos of various proce-
dures will allow easy incorporation of chemical peeling
techniques into your practice.
Once again, chemical peels have shown themselves
to be time-proven methods with unparalleled flexibil-
ity in their performance. Chemical peels have resurged
in popularity as courses and didactic sessions are once
again being offered to physicians. With a growing,
ethnically diverse population, we need a tool such as
chemical peels to allow us to treat every patient with any
skin type that comes to us seeking cosmetic enhance-
ment.
I am truly humbled and grateful to work with col-
leagues from all over the world on this edition, and I
thank them for their hard work in bringing to you an
exceptional textbook. I want to also recognize and
give special thanks to Meghan Andress at Elsevier for
the patience and guidance she offered all the authors.
Furthermore, our series editors, Murad Alam, MD, and
Jeffrey Dover, MD, deserve special recognition for their
tireless efforts in creating a series of textbooks focused
on cosmetic dermatology procedures and for their guid-
ance when the content of this book was being developed.
Lastly, to my family, thank you, thank you, thank
you! It was a busy year to say the least, but knowing I had
your support made it all worthwhile! I survived many
weekends and evenings of writing and editing but made
sure to get to all the important family celebrations and
school achievements. It was worth the effort!
I hope, as you read through this textbook, your inter-
est in peels is kindled and your desire to hone your skills
in this field is heightened. I am sure I speak on behalf
of all my coauthors when I say, once a “peeler” always a
“peeler.” Hopefully you will join us as a fellow “peeler”!
Sincerely,
Suzan Obagi, MD
vii
 LIST OF VIDEOS

 ideo 1. Alpha Hydroxy Acid Peel

V Video 8. Phenol Peeling - 4
Video 2. Salicylic Acid Peel Video 9. Blue Peel and Hetter VL Medium-Depth Peel
Video 3. TCA Peel - 1 Video 10. A combination of Microneedling and
Video 4. TCA Peel - 2 Chemical Peels for the Treatment of Acne Scars
Video 5. Phenol Peeling - 1 Video 11. Carbolic CROSS
Video 6. Phenol Peeling - 2 Video 12. Chemical Peel Over Facelift
Video 7. Phenol Peeling - 3 Video 13. A Medium-Depth TCA Peel on Dark Skin

ix
 PART 1 Introductory Chapters

1
The Chemistry of Peels: A
Hypothesis of Mechanism of
Action and Classification of Peels
Luc Dewandre, Alain Tenenbaum, Desmer Destang

A chemical peel is a treatment technique used to improve
and smooth the facial and/or body skin’s texture using a
chemical solution that causes the dead skin to slough off
and eventually peel off. The regenerated skin is usually
smoother, healthier, and less wrinkled than the old skin.
It is advised to seek training with a specialist such as
a dermatologist, plastic surgeon, otorhinolaryngologist
(facial plastic surgeon), or oral-maxillofacial surgeon
who is experienced in the specific types of peels you
wish to perform.
INTRODUCTION
This chapter proposes a classification of chemical peels
based on the mechanism of action of chemical peel solu-
tions. The traditionally accepted mechanism has been
based on the concept that the effect of a peeling solution
on the skin is based purely on its acidity. By using elemen-
tary concepts in chemistry, three separate mechanisms of
action for chemical peeling solutions are explained:
1. Acidity
2. Toxicity
3. Metabolic interactions
The literature devoted to chemical peels is full of
information about the methodology, indications, con-
traindications, side effects, and results obtained. With-
out any proof, acidity has always been assumed to be the
sole mechanism of action of peeling agents. All peeling
agents were assumed to induce the three stages of tissue
replacement: destruction, elimination, and regeneration,
all accompanied by a controlled stage of inflammation.
A brief study of the chemistry of the molecules and
solutions used in chemical peels immediately questions
the hypothesis that acidity is the only basis for the action
of peeling solutions. In fact, with the exception of tri-
chloroacetic acid (TCA) and nonneutralized glycolic
acid solutions, the most commonly used peeling solu-
tions are only weakly acidic, and phenol and resorcinol
mixtures may not be acidic at all, having a pH greater
than 7 in some formulations.
This chapter will discuss the elementary chemistry
concepts that, along with a review of the chemistry of
the skin, should help explain the possible interactions
between different peeling solutions and the skin. Finally,
two classifications of solutions for peelings will be pro-
posed, one according to their mechanisms of action
(classification of L. Dewandre) and the other according
to chemical parameters (structure of the molecule, pKa,
etc; or classification of A. Tenenbaum).
USEFUL ELEMENTS OF BASIC
CHEMISTRY
Understanding some of the basic concepts of chemistry
is necessary to truly understand chemical peels. Mineral
and organic chemistry are taught as biochemistry to
medical students, but most practicing physicians do not
remember these fundamental principles.
1
2 PART 1 Introductory Chapters
Also chemistry has been unfortunately neglected in
cosmetic dermatology and aesthetic medicine courses,
masters workshops, and congresses. A brief review of use-
ful information should help update most practitioners.
Acids
An acid (from the Latin acidus, meaning “sour”) is tradi-
tionally considered any chemical compound that, when dis-
solved in water, gives a solution with a hydrogen ion activity
greater than in pure water, i.e., a pH less than 7.0. That
approximates the modern definition of Johannes Nicolaus
Brønsted and Martin Lowry, who independently defined an
acid as a compound that donates a hydrogen ion (H+) to
another compound (called a base). Acid–base systems are
different from redox reactions in that there is no change in
oxidation state. Acids can occur in solid, liquid, or gaseous
form, depending on the temperature. They can exist as pure
substances or in solution. Chemicals or substances having
the property of an acid are said to be acidic (adjective).
Arrhenius Acids
The Arrhenius concept is the easiest one retained by
most peelers, because most peeling acids are ionic com-
pounds, acting as a source of H3O+ when dissolved in
water.
The Swedish chemist Svante Arrhenius attributed the
properties of acidity to hydrogen in 1884. An Arrhenius
acid is a substance that increases the concentration of
the hydronium ion, H3O+, when dissolved in water. This
definition stems from the equilibrium dissociation of
water into hydronium and hydroxide (OH−) ions:
H 2O( l )+ H 2O( l ) ⇌ H 3O +(aq)+ OH – (aq)
In pure water most molecules exist as H2O, but a small
number of molecules are constantly dissociating and
reassociating. Pure water is neutral with respect to acid-
ity or basicity, because the concentration of hydroxide
ions is always equal to the concentration of hydronium
ions. An Arrhenius base is a molecule that increases the
concentration of the hydroxide ion when dissolved in
water. Note that chemists often write H+(aq) and refer to
the hydrogen ion when describing acid–base reactions,
but the free hydrogen nucleus, a proton, does not exist
alone in water; it exists as the hydronium ion, H3O+.
Brønsted Acids
Although the Arrhenius concept is useful for describ-
ing many reactions, it is also quite limited in its scope.
Brønsted acids act by donating a proton to water and,
differently than Arrhenius acids, can also be used to
describe molecular compounds, whereas Arrhenius
acids must be ionic compounds.
In 1923 chemists Johannes Nicolaus Brønsted and
Thomas Martin Lowry independently recognized that
acid–base reactions involve the transfer of a proton. A
Brønsted–Lowry acid (or simply Brønsted acid) is a spe-
cies that donates a proton to a Brønsted–Lowry base.
Brønsted–Lowry acid–base theory has several advan-
tages over Arrhenius theory. Consider the following
reactions of acetic acid (CH3COOH) (used as a chemical
peel for the décolleté by some great peelers like L. Wiest),
the organic acid that gives vinegar its characteristic taste:
O OH2 O _
+
C O H C O OH2
H3C H3C
H
O NH3 O _ +
C O H C O NH2
H3C H3C
H
Both theories easily describe the first reaction:
CH3COOH acts as an Arrhenius acid because it acts as
a source of H3O+ when dissolved in water, and it acts
as a Brønsted acid by donating a proton to water. In the
second example CH3COOH undergoes the same trans-
formation, donating a proton to ammonia (NH3), but it
cannot be described using the Arrhenius definition of an
acid because the reaction does not produce hydronium.
As with the acetic acid reactions, both definitions
work for the first example, where water is the solvent
and a hydronium ion is formed. The next reaction does
not involve the formation of ions but can still be viewed
as a proton transfer reaction.
Lewis Acids
The Brønsted–Lowry definition is the most widely used
definition; unless otherwise specified, acid–base reac-
tions are assumed to involve the transfer of a proton
(H+) from an acid to a base.
A third concept was proposed by Gilbert N. Lewis
that includes reactions with acid–base characteristics
that do not involve a proton transfer. A Lewis acid is a
species that accepts a pair of electrons from another spe-
cies; in other words, it is an electron pair acceptor. Brøn-
sted acid–base reactions are proton transfer reactions,
 CHAPTER 1 The Chemistry of Peels: A Hypothesis of Mechanism of Action
whereas Lewis acid–base reactions are electron pair
transfers. All Brønsted acids are also Lewis acids, but
not all Lewis acids are Brønsted acids. Contrast the fol-
lowing reactions, which could be described in terms of
acid–base chemistry:
F F
- -
B F F B F concentration of H2O. The acid dissociation constant Ka
F F
F
H
+ +
N H H N H [HA]
H H
H H
In the first reaction a fluoride ion, F−, gives up an
electron pair to boron trifluoride to form the product
tetrafluoroborate. Fluoride “loses” a pair of valence elec-
trons because the electrons shared in the B–F bond are
located in the region of space between the two atomic
nuclei and are therefore more distant from the fluoride
nucleus than they are in the lone fluoride ion. BF3 is
a Lewis acid because it accepts the electron pair from
fluoride. This reaction cannot be described in terms of
Brønsted theory, because there is no proton transfer. The
second reaction can be described using either theory. A
proton is transferred from an unspecified Brønsted acid
to ammonia, a Brønsted base; alternatively, ammonia
acts as a Lewis base and transfers a lone pair of electrons
to form a bond with a hydrogen ion. The species that
gains the electron pair is the Lewis acid; for example, the
oxygen atom in H3O+ gains a pair of electrons when one
of the H–O bonds is broken and the electrons shared
in the bond become localized on oxygen. Depending
on the context, Lewis acids may also be described as a
reducing agent or an electrophile.
Dissociation and Equilibrium
Reactions of acids are often generalized in the form
HA ⇌ H+ + A−, where HA represents the acid and A− is
the conjugate base. Acid–base conjugate pairs differ by
one proton and can be interconverted by the addition
or removal of a proton (protonation and deprotonation,
3
respectively). Note that the acid can be the charged spe-
cies and the conjugate base can be neutral, in which
case the generalized reaction scheme could be written
as HA ⇌ H+ + A. In solution there exists an equilibrium
between the acid and its conjugate base. The equilibrium
constant K is an expression of the equilibrium concen-
trations of the molecules or the ions in solution. Brack-
ets indicate concentration, such that [H2O] means the
is generally used in the context of acid–base reactions.
The numerical value of Ka is equal to the concentration
of the products divided by the concentration of the reac-
tants, where the reactant is the acid (HA) and the prod-
ucts are the conjugate base and H+.
[H +] [A −]
Ka =
The stronger of two acids will have a higher Ka
than the weaker acid; the ratio of hydrogen ions
to acid will be higher for the stronger acid because
the stronger acid has a greater tendency to lose its
proton. Because the range of possible values for Ka
spans many orders of magnitude, a more manageable
constant, pKa, is more frequently used, where pKa
= −log10Ka. Stronger acids have a smaller pKa than
weaker acids. Experimentally determined pKa at 25°C
in aqueous solution are often quoted in textbooks and
reference material.
Acid Strength
For peelers, the notion of acid strength is very import-
ant, because stronger acids have a higher Ka and a lower
pKa than weaker acids.
For our classification, two parameters have to be
taken into consideration for peelers:
1. The pKa, a synonym of the acid’s strength.
2. The pH, a synonym of the penetration for the selected
acid.
For chemists, the strength of an acid refers to its abil-
ity or tendency to lose a proton. A strong acid is one
that completely dissociates in water; in other words, one
mole of a strong acid, HA, dissolves in water, yielding
one mole of H+ and one mole of the conjugate base, A−,
and none of the protonated acid HA. In contrast a weak
acid only partially dissociates, and at equilibrium both
the acid and the conjugate base are in solution. In water
each of these essentially ionizes 100%. The stronger an
4 PART 1 Introductory Chapters
acid is, the more easily it loses a proton, H+. Two key
factors that contribute to the ease of deprotonation are
the polarity of the H–A bond and the size of atom A,
which determines the strength of the H–A bond. Acid
strengths are also often discussed in terms of the stabil-
ity of the conjugate base.
Caution is advised against simply classifying “cos-
metic peels” for acids with pKa > 3 and “medical peels”
for acids with pKa < 3, because some acids like phenol
can be toxic substances even with a pKa > 3.
Polarity and the Inductive Effect
The polarity of the H–A bond is the first factor contribut-
ing to acid strength.
As the electron density on hydrogen decreases, it
becomes more acidic. Moving from left to right across a
row on the periodic table, elements become more elec-
tronegative (excluding the noble gases).
In several compound classes, collectively called car-
bon acids, the C–H bond can be sufficiently acidic for
proton removal. Inactivated C–H bonds are found in
alkanes and are not adjacent to a heteroatom (O, N, Si,
etc.). Such bonds usually only participate in radical sub-
stitution.
Polarity refers to the distribution of electrons in a
bond, the region of space between two atomic nuclei
where a pair of electrons is shared. When two atoms
have roughly the same electronegativity (ability to
attract electrons), the electrons are shared evenly and
spend equal time on either end of the bond. When
there is a significant difference in electronegativities of
two bonded atoms, the electrons spend more time near
the nucleus of the more electronegative element and an
electrical dipole, or separation of charges, occurs, such
that there is a partial negative charge localized on the
electronegative element and a partial positive charge on
the electropositive element. Hydrogen is an electropos-
itive element and accumulates a slightly positive charge
when it is bonded to an electronegative element such as
oxygen or chlorine.
The electronegative element need not be directly
bonded to the acidic hydrogen to increase its acidity.
An electronegative atom can pull electron density out
of an acidic bond through the inductive effect. The elec-
tron-withdrawing ability diminishes quickly as the elec-
tronegative atom moves away from the acidic bond.
Carboxylic acids are organic acids that contain an
acidic hydroxyl group and a carbonyl (C–O bond).
Carboxylic acids can be reduced to the corresponding
alcohol; the replacement of an electronegative oxygen
atom with two electropositive hydrogens yields a prod-
uct that is essentially nonacidic. The reduction of acetic
acid to ethanol using LiAlH4 (lithium aluminum hydride
or LAH), and ether is an example of such a reaction.
H H H
O LAH
C
H C C H C OH
OH ether
H H H
The pKa for ethanol is 16, compared with 4.76 for
acetic acid.
Atomic Radius and Bond Strength
The size of the atom A or atomic radius is the second fac-
tor contributing to acid strength.
Moving down a column on the periodic table, atoms
become less electronegative but also significantly larger,
and the size of the atom tends to dominate its acidity
when sharing a bond to hydrogen.
Hydrogen sulfide, H2S, is a stronger acid than water,
even though oxygen is more electronegative than sulfur.
This is because sulfur is larger than oxygen and the H–S
bond is more easily broken than the H–O bond.
Another factor that contributes to the ability of an
acid to lose a proton is the strength of the bond between
the acidic hydrogen and the atom that bears it. This, in
turn, is dependent on the size of the atoms sharing the
bond. For an acid HA, as the size of atom A increases, the
strength of the bond decreases, meaning that it is more
easily broken, and the strength of the acid increases.
Chemical Characteristics
It is important to keep in mind the difference between
monoprotic acids (having one unique pKa) and polyprotic
acids (having two or more pKa).
Monoprotic Acids
Monoprotic acids are those acids that are able to donate
one proton per molecule during the process of disso-
ciation (sometimes called ionization), as shown below
(symbolized by HA):
HA(aq)+ H 2O(1) ⇌ H 3O + (aq)+A–(aq)Ka
Common examples of monoprotic acids in organic
acids indicate the presence of one carboxyl group,
 CHAPTER 1 The Chemistry of Peels: A Hypothesis of Mechanism of Action
and mostly these acids are known as monocarboxylic
acid. Examples in organic acids include acetic acid
(CH3COOH), glycolic acid, and lactic acid.
Polyprotic Acids
Polyprotic acids are able to donate more than one pro-
ton per acid molecule, in contrast to monoprotic acids
that only donate one proton per molecule. Specific types
of polyprotic acids have more specific names, such
as diprotic acid (two potential protons to donate) and
triprotic acid (three potential protons to donate).
A diprotic acid (here symbolized by H2A) can
undergo one or two dissociations depending on the pH.
Each dissociation has its own dissociation constant, Ka1
and Ka2.
H 2A (aq) + H 2O (1) ⇌ H 3O + (aq) + HA− (aq) K a1
HA− (aq) + H 2O( l ) ⇌ H 3O +(aq) + A2 −(aq) K a2
The first dissociation constant is typically greater than
the second; i.e., Ka1 > Ka2. For example, the weak unstable
carbonic acid (H2CO3) can lose one proton to form bicar-
bonate anion (HCO3−) and lose a second to form carbon-
ate anion (CO32−). Both Ka values are small, but Ka1 > Ka2.
Diprotic acids used for peelings are malic, tartaric,
and azelaic acids.
5
Two dissociations mean that such acids can gen-
erate two peelings, depending on the pH, with the
second one less acidic than the first one. In this case,
we consider one peeling reaction per one dissocia-
tion.
A triprotic acid (H3A) can undergo one, two, or
three dissociations and has three dissociation constants,
where Ka1 > Ka2 > Ka3.
H 3A (aq) + H 2O ( l ) ⇌ H 3O +(aq) + H 2A – (aq) K a1
2A (aq) H 2O ( l ) H 3O (aq) HA (aq) K a2
HA2 – (aq) + H 2O( l ) ⇌ H 3O + (aq) + A3 – (aq) K a3
An organic example of a triprotic acid is citric acid,
which can successively lose three protons to finally form
the citrate ion. Even though the positions of the protons
on the original molecule may be equivalent, the succes-
sive Ka values will differ, because it is energetically less
favorable to lose a proton if the conjugate base is more
negatively charged.
Weak Acid–Weak Base Equilibria
To lose a proton, it is necessary that the pH of the system
rise above the pKa of the protonated acid. The decreased
concentration of H+ in that basic solution shifts the
equilibrium toward the conjugate base form (the depro-
tonated form of the acid). In lower-pH (more acidic)
solutions, there is a high enough H+ concentration in
the solution to cause the acid to remain in its protonated
6 PART 1 Introductory Chapters
form, or to protonate its conjugate base (the deproton-
ated form).
Solutions of weak acids and salts of their conjugate
bases form buffer solutions.
Buffer Solution
A buffer solution is an aqueous solution consisting of
a mixture of a weak acid and its conjugate base or a
weak base and its conjugate acid. The property of buffer
solutions is that the pH of the solution changes very
little when a small amount of acid or base is added to
it. Buffer solutions are used as a means of keeping pH
at a nearly constant value in a wide variety of chemi-
cal applications. Many life forms thrive only in a rela-
tively small pH range; an example of a buffer solution
is blood.
Le Chatelier’s Principle
In a solution there is an equilibrium between a weak
acid, HA, and its conjugate base, A−:
+ –
HA + H 2O ⇌ H 3O + A
• W hen hydrogen ions (H+) are added to the solution,
equilibrium moves to the left, as there are hydrogen
ions (H+ or H3O+) on the right-hand side of the equi-
librium expression.
• When hydroxide ions (OH−) are added to the solu-
tion, equilibrium moves to the right, as hydrogen
ions are removed in the reaction (H+ + OH− →
H2O).
Thus, in both cases, some of the added reagent is con-
sumed in shifting the equilibrium in accordance with Le
Chatelier’s principle, and the pH changes by less than it
would if the solution were not buffered.
Henderson–Hasselbach Equation
The acid dissociation constant for a weak acid, HA, is
defined as:
[H + ] [A − ]
Ka =
[HA]
Simple manipulation with logarithms gives the Hen-
derson–Hasselbach equation, which describes pH in
terms of pKa:
[A − ]
pH =pK a + log10
[HA]
In this equation [A−] is the concentration of the
conjugate base and [HA] is the concentration of the
acid. It follows that when the concentrations of acid
and conjugate base are equal, often described as
half-neutralization, pH = pKa. In general, the pH of
a buffer solution may be easily calculated, knowing
the composition of the mixture, by means of an ICE
table. An ICE (initial, change, equilibrium) table is
a simple matrix formalism that used to simplify the
calculations in reversible equilibrium reactions (e.g.,
weak acids and weak bases or complex ion forma-
tion).
One should remember that the calculated pH may be
different from measured pH.
Buffer Capacity
Buffer capacity (Fig. 1.1) is a quantitative measure of
the resistance of a buffer solution to pH change with the
addition of hydroxide ions. It can be defined as follows:
dn
Buffer capacity=
d (pH)
where dn is an infinitesimal amount of added base
and d(pH) is the resulting infinitesimal change in
pH. With this definition the buffer capacity can be
expressed as:
dn Kw CA K a [H + ]
=2.303 + [H + ] + 2
d ( pH) [H + ] (K a + [H + ])
where Kw is the self-ionization constant of water and
CA is the analytical concentration of the acid, equal
to [HA] + [A−]. The term Kw/[H+] becomes significant
at pH greater than about 11.5, and the second term
becomes significant at pH less than about 2. Both these
terms are properties of water and are independent of
the weak acid. Considering the third term, it follows
that:
1. Buffer capacity of a weak acid reaches its maximum
value when pH = pKa.
2. At pH = pKa ± 1 the buffer capacity falls to 33%
of the maximum value. This is the approximate
range within which buffering by a weak acid is
effective. Note: at pH = pKa − 1, the Hender-
son–Hasselbach equation shows that the ratio
[HA]:[A−] is 10:1.
3. Buffer capacity is directly proportional to the analyt-
ical concentration of the acid.
 CHAPTER 1 The Chemistry of Peels: A Hypothesis of Mechanism of Action
100
80
Buffer capacity (%)
60
40
20
0
4 5 6 7 8 9
pH
Fig. 1.1 Buffer capacity for pKa = 7 as a percentage of maxi-
mum.
Current Applications of Buffer Solutions
Their resistance to changes in pH makes buffer solutions
very useful for chemical manufacturing and essential for
many biochemical processes. The ideal buffer for a par-
ticular pH has a pKa equal to that pH, since such a solu-
tion has maximum buffer capacity.
Buffer solutions are necessary to keep the correct
physiological pH for enzymes in many organisms to
work. A buffer of carbonic acid (H2CO3) and bicarbon-
ate (HCO3−) is present in blood plasma, to maintain a
pH between 7.35 and 7.45.
The majority of biological samples used in research
are made in buffers, specifically phosphate-buffered
saline (PBS) at pH 7.4.
Buffered TCA are more likely to create dyschromias.
Useful Buffer Mixtures
• Citric acid, sodium citrate, pH range 2.5 to 5.6.
• Acetic acid, sodium acetate, pH range 3.7 to 5.6.
Neutralization
There is among physicians a big confusion between
a buffered peel (see above) and a neutralized peel. In
chemistry, neutralization is a chemical reaction whereby
an acid and a base react to form water and a salt.
In an aqueous solution, solvated hydrogen ions
(hydronium ions, H3O+) react with hydroxide ions
(OH−) formed from the alkali to make two molecules
7
of water. A salt is also formed. In nonaqueous reactions,
water is not always formed; however, there is always a
donation of protons (see Brønsted–Lowry acid–base
theory).
Often, neutralization reactions are exothermic, giving
out heat to the surroundings (the enthalpy of neutraliza-
tion). On the other hand, an example of endothermic
neutralization is the reaction between sodium bicarbon-
ate (baking soda) and any weak acid—for example, ace-
tic acid (vinegar).
Neutralization of the chemical peeling agent is an
important step, the timing of which is determined by
either the frost in the skin or how much contact time
10 the peel has with the skin. Neutralization is achieved
by a majority of peelers applying cold water or wet,
cool towels to the face following the frost. According
to physical chemistry, using water just after the frost
provokes an exothermic reaction that can provoke
a “cold” burn. Other neutralizing agents that can be
used include bicarbonate spray or soapless cleansers.
Peeling agents for which this neutralization step is less
important include salicylic acid, Jessner’s solution,
TCA, and phenol.
In partially neutralized alpha-hydroxy acid (AHA)
solutions, the acid and a lesser amount of base are
combined in a reversible chemical reaction that yields
unneutralized acid and a salt.
The resulting solution has less free acid and a higher
pH than a solution that has not been neutralized. In par-
tially neutralized formulations, the salt functions as a
reservoir of acid that is available for second-phase pen-
etration. This means that partially neutralized formulas
can deliver as much, if not more, AHA than free acid
formulas, but in a safer, “time-released” manner. There-
fore the use of partially neutralized glycolic acid solu-
tions seems prudent, because they have a better safety
profile than low-pH solutions containing only free gly-
colic acid.
Clinical studies have shown that a partially neutral-
ized lactic acid preparation improves the skin, both in
appearance and histologically. Other studies using skin
tissue cultures showed that partially neutralized glycolic
acid stimulates fibroblast proliferation—an index of tis-
sue regeneration. Looking at electrical conductance of
the skin (an indicator of water content or moisturiza-
tion), higher pH products (those that have been par-
tially neutralized) are better moisturizers than lower pH
preparations.
8 PART 1 Introductory Chapters
0.45 mm
Stratum papillare
Stratum reticulare
Fig. 1.2 Anatomy of the skin with penetration depths of the various peels: green, superficial peels; blue,
medium-depth peels; and red, deep peels.
ANATOMY OF THE SKIN
Like the whole human organism, the skin can be con-
sidered an aqueous solution into which are dissolved a
certain number of molecules (Fig. 1.2). These are mol-
ecules of proteins, lipids, and carbohydrates in variable
quantities and proportions.
There is more water in the dermis than in the epider-
mis. This is due to the presence of blood, glycosamino-
glycans (GAGs), and lymph in the dermis, all of which
have a high water content, as well as the fact that the
epidermis is in contact with a more or less dehydrated
environment.
There are more proteins (keratin) in the epidermis
than in the dermis, whereas more carbohydrates and
lipids exist in the dermis, and there are even more in the
subcutaneous layer than in the dermis.
0.06 mm 0.6 mm
The most important molecule in the epidermis is a
fibrous and corneal protein, keratin, that protects and
takes part, through its continuous production by the
keratinocytes, in the complete replacement of the epi-
dermis every 27 days.
The most important molecules of the dermis are
collagen, elastin, GAGs, and the proteoglycans. Col-
lagen and elastin are proteins, whereas GAGs (e.g.,
hyaluronic acid) and the proteoglycans are biolog-
ical polymers formed mainly by sugars that retain
water.
Collagen constitutes the skin’s structural resource
and is the most abundant protein in the human body. It
is formed mainly by glycine, proline, and hydroxypro-
line. It is one of the most resistant natural proteins and
helps give the skin structural support. Elastin is similar
to collagen, but it is an extensible protein responsible for
 CHAPTER 1 The Chemistry of Peels: A Hypothesis of Mechanism of Action
elasticity; hence its name. It has two unique polypep-
tides, desmosine and isodesmosine.
The GAGs contain specific sugars such as glucos-
amine sulfate, N-acetylglucosamine, and glucosamine
hydrochloride, all very capable of attracting water.
They form long chains of molecules, such as hyal-
uronic acid, keratin sulfate, heparin, dermatin, and
chondroitin, that retain up to 1000 times their weight
in water.
The hypodermis or subcutaneous tissue consists
mainly of fat, although this tissue accounts for a com-
pletely different chemical interaction with peeling solu-
tions. Chemical peels are not meant to extend down into
the subcutaneous layer, so this is not discussed.
The different molecular composition of the differ-
ent levels of the skin may explain the variability of the
interactions and the results obtained. These benefits are
correlated to the penetration level achieved when using
a given peeling agent.
It is likewise for the pH. Although the pH of the
epidermis is a well-established number, the pH of the
dermis is not an exact value and has been difficult to
measure precisely.
The epidermal acid layer or mantel is the result of
sebum secretion and sweat. It protects the skin and
makes it less vulnerable from attacks by microorganisms
such as bacteria and fungi. A healthy epidermis has a
slightly acidic pH with a range between 4.2 and 5.6. It
varies from one part of the skin to another and, in gen-
eral, is more acidic in men than in women.
The pH of the epidermis also varies depending on its
different layers. For a “skin” pH of around 5 we will find
a pH near 5.6 in the corneal layer and one of 4.8 in the
deep layers of the epidermis, which are rich in corneo-
cytes and melanocytes. Finally, dry skin is more acidic
than oily skin, which can reach pH 6.
Because the dermis contains a significant amount of
fluid and blood, we can presume the pH to be 6 to 6.5,
and it is slightly less acidic than the epidermis, with a
pH of 6 for the papillary dermis and 7 for the vascular
reticular dermis.
Skin Basic Chemistry
The approximate skin composition is seen in Box 1.1.
Acids and Cell Membranes
Cell membranes contain fatty acid esters such as
phospholipids. Fatty acids and fatty acid derivatives
9
BOX 1.1 Approximate Skin Composition
Water 70%
Proteins 25.5%
Lipids 2.0%
Oligo mineral elements 0.5% (e.g., zinc, copper, se-
lenium)
Carbon hydrates 2.0% (mucopolysaccharides)
are another group of carboxylic acids that play a sig-
nificant role in biology. These contain long hydro-
carbon chains and a carboxylic acid group on one
end. The cell membrane of nearly all organisms
is primarily made up of a phospholipid bilayer, a
micelle of hydrophobic fatty acid esters with polar,
hydrophilic phosphate “head” groups. Membranes
contain additional components, some of which can
participate in acid–base reactions. Cell membranes
are generally impermeable to charged or large, polar
molecules because of the lipophilic fatty acyl chains
comprising their interior. Many biologically import-
ant molecules, including a number of pharmaceuti-
cal agents, are organic weak acids that can cross the
membrane in their protonated, uncharged form but
not in their charged form (i.e., as the conjugate base).
The charged form, however, is often more soluble
in blood and cytosol, both aqueous environments.
When the extracellular environment is more acidic
than the neutral pH within the cell, certain acids will
exist in their neutral form and will be membrane
soluble, allowing them to cross the phospholipid
bilayer. Acids that lose a proton at the intracellu-
lar pH will exist in their soluble, charged form and
are thus able to diffuse through the cytosol to their
target.
BASIC CHEMISTRY OF THE MOST
USED MOLECULES IN SOLUTIONS FOR
CHEMICAL PEELINGS
It is interesting to consider the chemical nature of the
molecules most commonly found in chemical peels. In
the case of the alpha-hydroxy acids, the acid carboxyl
group is on the first carbon (C1) and the hydroxyl is on
the alpha carbon (C2). Salicylic acid is a beta-hydroxy
acid with the hydroxyl group on C3.
10 PART 1 Introductory Chapters
How the Most Commonly Used Substances
in Chemical Peel Solutions Work—A
Hypothesis
Based on their different properties and the ways in
which they work, L. Dewandre divides the substances
most used for chemical peels into three categories: met-
abolic, caustic, and toxic (Table 1.1).
SUBSTANCES WITH MAINLY METABOLIC
ACTIVITY
With the exception of glycolic and lactic acids, the met-
abolic substances described in the following sections are
not used, properly speaking, in the solutions involved in
chemical peels. Today, glycolic and lactic acids are nearly
ubiquitous in medical cosmetology as a part of skin care
regimens and in the office as chemical peel procedures.
Alpha Hydroxy Acids
The AHAs are a class of chemical compounds that con-
sist of a carboxylic acid with a hydroxy group on the
adjacent carbon. They may be either naturally occurring
or synthetic. AHAs are well known for their use in the
cosmetics industry. They are often found in products
claiming to reduce wrinkles or the signs of aging and
improve the overall look and feel of the skin. They are
also used as chemical peels available in a dermatologist’s
office, beauty and health spas, and home kits, which usu-
ally contain a lower concentration. Although their effec-
tiveness is documented, numerous cosmetic products
have appeared on the market with unfounded claims of
performance. Many well-known AHAs are useful build-
ing blocks in organic synthesis: the most common and
simple are glycolic acid, lactic acid, citric acid, and man-
delic acid.
AHA peels include aliphatic (lactic, glycolic, tartaric,
and malic) and aromatic (mandelic) acids that are syn-
thesized chemically for use in peels. Various concentra-
tions can be purchased, with 10% to 70% concentration
used for facial peels, most commonly 50% or 70%. AHAs
are weak acids that induce their rejuvenation activity by
either metabolic or caustic effect. At low concentration
(<30%), they reduce sulfate and phosphate groups from
the surface of corneocytes. By decreasing corneocyte
cohesion, they induce exfoliation of the epidermis. At
higher concentration, their effect is mainly destructive.
Because of the low acidity of AHAs, they do not induce
enough coagulation of the skin proteins and therefore
cannot neutralize themselves. They must be neutralized
using a weak buffer.
Knowledge of the skin structure within the frame-
work of cutaneous aging is helpful to understand the
topical action of AHAs. Human skin has two principal
components, the avascular epidermis and the under-
lying vascular dermis. Cutaneous aging, though it has
epidermal involvement, seems to involve primarily the
dermis and is caused by both intrinsic and extrinsic
aging factors.
AHAs most commonly used in cosmetic applications
are typically derived from fruit products including gly-
colic acid (sugar cane), lactic acid (sour milk), malic
acid (apples), citric acid (citrus fruits) and tartaric acid
(grapes and wine). For any topical compound, includ-
ing AHA, it must penetrate into the skin, where it can
act on living cells. Bioavailability (influenced primar-
ily by small molecular size) is one characteristic that
is important in determining the compound’s ability to
penetrate the top layer of the skin. Glycolic acid hav-
ing the smallest molecular size is the AHA with greatest
bioavailability and penetrates the skin most easily; this
largely accounts for the popularity of this product in
cosmetic applications.
• Epidermal effects: AHAs have a profound effect on
keratinization, which is clinically detectable by the
formation of a new stratum corneum. It appears that
AHAs modulate this formation through diminished
cellular cohesion between corneocytes at the lowest
levels of the stratum corneum.
• Dermal effects: AHAs with greater bioavailabil-
ity appear to have deeper dermal effects. Glycolic
acid, lactic acid, and citric acid, on topical appli-
cation to photodamaged skin, have been shown to
produce increased amounts of mucopolysaccha-
rides and collagen and increased skin thickness
without detectable inflammation, as monitored by
skin biopsies.
AHAs are generally safe when used on the skin as
a cosmetic agent using the recommended dosage. The
most common side effects are mild skin irritation, red-
ness, and flaking. The severity usually depends on the
pH and the concentration of the acid used.
The Food and Drug Administration (FDA) has also
warned consumers that care should be taken when
using AHAs after an industry-sponsored study found
that they can increase photosensitivity to the sun.
 CHAPTER 1 The Chemistry of Peels: A Hypothesis of Mechanism of Action
TABLE 1.1 Classification of Chemical Peels (A. Tenenbaum)
Acids Acids pKa >3 from Lower to Classification of L. Number of
Category Subcategory Higher pKa = 3 pKa <3 pKa1 pKa2 pKa3 Dewandre Reactions
Alpha hydroxy Aliphatic Tartaric 3.04 4.37 Metabolic Diprotic
Citric 3.15 4.77 6.40 Metabolic Triprotic
Malic 3.40 5.13 Metabolic Diprotic
Glycolic 3.83 Metabolic Monoprotic
Lactic 3.86 Metabolic Monoprotic
Aromatic Mandelic 3.37 Metabolic Monoprotic
TXA 4.3 Monoprotic
Alpha keto Pyruvic 2.49 Not available Monoprotic
Bicarboxylic Azelaic 4.55 5.59 Metabolic Diprotic
Beta Hydroxy Salicylic 2.97 Toxic Monoprotic
TCA TCA 0.53 Caustic Monoprotic
Phenol Aromatic Phenol 9.95 Toxic Alcohol > acid
TCA, Trichloroacetic acid; TXA, tranexamic acid.

11
12 PART 1 Introductory Chapters
Comparison of the pH to the pKa: The Interesting
Cosmetic Actions of the Alpha-Hydroxy Acids
• For a pH greater than the pKa, the AHAs are essentially
moisturizers. The main differences between the mois-
turizing and caustic effects are related to the degree
of neutralization of the AHA molecules. Neutralizing
the AHA with sodium or ammonium creates a salt
with more moisturizing and less caustic effect.
• For a pH less than or equal to the pKa, the AHAs are
keratoregulators that increase skin exfoliation and cell
replacement. In such case, the acid form is preponder-
ant, which is more absorbed and facilitates penetration.
Their antiaging action can be compared with reti-
noids, but their mechanism of action is different. They
interfere with certain kinds of enzymes (sulfotransfer-
ases, phosphotransferases, kinases) whose function is to
fix the sulfate and phosphate groups to the surface of the
corneocytes. The reduction of these groups involves a
decrease in electronegativity and corneocyte cohesion,
which leads to a breaking away of the cells from each
other, creating exfoliation and flaking. This activity can
be characterized as a metabolic action. However, when
used in strong concentrations of 30% to 70% free acid
in aqueous solution for peeling, their effect is based on
their acidity and results in destruction.
Aliphatic Alpha Hydroxy Acids (Glycolic,
Lactic, Malic, Tartaric, Citric) With pKa >3
Glycolic Acid (pKa = 3.83) and Its Different
Concentrations
Abbreviation: GA
O
OH
HO
Properties:
• Molecular formula: C2H4O3
• Molar mass: 76.05 g/mol
• Appearance: white, powdery solid
• Density: 1.27 g/cm3
• Solubility in water: 70% solution
• Solubility in other solvents: alcohols, acetone, acetic
acid, and ethyl acetate
• Acidity (pKa): 3.83
Glycolic acid (or hydroxyacetic acid) is the smallest
AHA. This colorless, odorless, and hygroscopic crystal-
line solid is highly soluble in water. It is used in various
skin care products.
Formulated from sugar cane, glycolic acid creates
a mild exfoliating action. Glycolic acid peels work by
loosening up the horny layer and exfoliating the superfi-
cial top layer. This peel also stimulates collagen growth.
Once applied, glycolic acid reacts with the upper
layer of the epidermis, weakening the binding proper-
ties of the lipids that hold the dead skin cells together.
This allows the outer skin to “dissolve,” revealing the
underlying skin.
In low concentrations, 5% to 10%, glycolic acid
reduces cell adhesion in the top layer of the skin. This
action promotes exfoliation of the outermost layer of the
skin, accounting for smoother texture following regular
use of topical glycolic acid. This relatively low concentra-
tion of glycolic acid lends itself to daily use as a mono-
therapy or a part of a broader skin care management for
such conditions as acne, photo-damage, and wrinkling.
Care needs to be taken to avoid irritation, as this may
result in worsening of any pigmentary problems. Newer
formulations combine glycolic acid with an amino acid
such as arginine and form a time-release system that
reduces the risk of irritation without affecting glycolic
acid efficacy. The use of an anti-irritant like allantoin is
also helpful. Because of its safety, glycolic acid at con-
centrations below 10% can be used daily by most people
except those with very sensitive skin.
In medium concentrations, between 10% and 50%, its
benefits are more pronounced but are limited to tempo-
rary skin smoothing without much long-lasting results.
This is still a useful concentration to use because it can
prepare the skin for more efficacious glycolic acid peels
at higher concentrations (50%–70%) as well as to prime
the skin for deeper chemical peels such as TCA peel.
At higher concentrations (called here high concentra-
tions), 50% to 70% applied for 3 to 8 minutes (usually
done by a physician), glycolic acid promotes disruption
of the bonds between the keratinocytes and can be used
to treat acne or photo damage (such as mottled dyspig-
mentation, or fine wrinkles). The benefits from such
short contact application (chemical peels) depend on
the pH of the solution (the more acidic the product, or
lower pH, the more pronounced the results), the con-
centration of GA (higher concentrations produce more
vigorous response), the length of application, and prior
skin conditioning such as prior use of topical retinoids.
Although single application of 50% to 70% GA will pro-
duce beneficial results, multiple treatments every 2 to 4
weeks are required for optimal results. It is important
 CHAPTER 1 The Chemistry of Peels: A Hypothesis of Mechanism of Action
to understand that glycolic acid peels are chemical peels
with similar risks and side effects as other peels.
Lactic Acid (pKa = 3.86)
Lactic acid is derived from either sour milk or bilber-
ries. This peel will remove dead skin cells and promote
healthier, softer, and more radiant skin.
O of a pKa3 = 6.40.
OH
Properties:
• Molecular formula: C3H6O3
• Molar mass: 90.08 g/mol
• Acidity (pKa): 3.86 at 25°C
In our opinion, glycolic and lactic peel solutions must
have a pH between 1.5 and 2.5 in order to combine a source
of inflammation and stimulation, with their metabolic
effects being, essentially, the turnover of epidermal cells.
Malic Acid (pKa1 = 3.4, pKa2 = 5.13)
O OH
OH
HO
O ical community as an antibacterial agent, particularly
This peel is the same type of mildly invasive peel derived
from the extracts of apples. It can open up the pores,
allow the pores to expel their sebum, and reduce acne.
Tartaric Acid (pKa1 = 3.04, pKa2 = 4.37)
OH O ecule than glycolic acid, which makes it better tolerated
HO
OH
O OH
This is derived from grape extract and is capable of
delivering the same benefits as the above peels.
Citric Acid (pKa1 = 3.15, pKa2 = 4.77, pKa3 = 6.40)
O OH
O O
HO OH
OH
Citric acid is usually derived from lemons, oranges,
limes, and pineapples. These peels are simple and
13
effective, though not incredibly invasive or capable of
significant improvement with one treatment.
The citric acid is triprotic, having three pKa values.
It is quite interesting, because the first pKa is lower than
the pKa of the monoprotic glycolic acid on one hand,
and the three reactions are made of two peelings (pKa1 =
3.15, pKa2 = 4.77) that end with a buffer (third reaction)
We can easily understand that citric acid used for
peelings does not need any neutralization or a buffer.
Aromatic Alpha Hydroxy Acid with pKa >3
Mandelic Acid: An Aromatic Alpha Hydroxy Acid
(pKa = 3.37)
HO
OH
O
Mandelic acid is an aromatic AHA with the molecular
formula C8H8O3. It is a white crystalline solid that is sol-
uble in water and most common organic solvents.
Mandelic acid has a long history of use in the med-
in the treatment of urinary tract infections. It has also
been used as an oral antibiotic. Lately, mandelic acid
has gained popularity as a topical skin care treatment
for adult acne. It is also used as an alternative to glycolic
acid in skin care products. Mandelic acid is a larger mol-
on the skin. Mandelic acid is also advantageous in that it
possesses antibacterial properties, whereas glycolic acid
does not.
Its use as a skin care modality was pioneered by
James E. Fulton, who helped develop retinoic acid
(tretinoin, Retin A) in 1969 with his mentor, Albert
Kligman, at the University of Pennsylvania. On the
basis of this research, dermatologists now suggest
mandelic acid as an appropriate treatment for a wide
variety of skin pathologies, from acne to wrinkles; it is
especially good in the treatment of adult acne because
it addresses both of these concerns. Mandelic acid is
also recommended as a prelaser and postlaser resur-
facing treatment, reducing the amount and length of
irritation.
14 PART 1 Introductory Chapters
Mandelic acid peels are commercialized nowadays
as gels with a specific viscosity, which make them user
friendly for beginners.
Alpha Keto Acids With pKa <3
Pyruvic Acid: An Alpha Keto Acid (pKa = 2.49)
O peelings may need to be neutralized but does not need
OH
O enzymes, including 5-alpha reductase, the enzyme respon-
A solution of 40% to 50% pyruvic acid in ethanol is the
most-used pyruvate in current practice.
Pyruvic acid is a ketone as well as the simplest alpha-
keto acid. The carboxylate (COOH) ion (anion) of pyru-
vic acid, CH3COCOO−, is known as pyruvate and is a
key intersection in several metabolic pathways.
It is often used to treat mild to moderate papulopustu-
lar acne with concentrations between 40% and 50% every
2 weeks for a total of 3 to 4 months. It reduces the sebum
levels and does not affect the cutaneous hydration.
Bi Carboxylic Acid With pKa >3
Azelaic Acid (pKa1 = 4.550, pKa2 = 5.598)
O O
HO OH
Azelaic acid or 1,7-heptanedicarboxylic acid is a satu-
rated dicarboxylic acid naturally found in wheat, barley,
and rye. It is active in a concentration of 20% in topical
products used in a number of skin conditions, mainly
mild to moderate acne and papulopustular rosacea. It
works in part by inhibiting the growth of skin bacteria
that cause acne and by keeping skin pores clear.
It has some interesting properties:
• Antibacterial: It reduces the growth of bacteria in the
follicle (Propionibacterium acnes, Staphylococcus epi-
dermis)
• Keratolytic and comedolytic: It returns to normal the
disordered growth of the skin cells, lining the follicle.
• Scavenger of free radicals and reduces inflammation
• Reduces pigmentation by acting as a weak tyrosinase
inhibitor
• Nontoxic and is well tolerated by most patients
Azelaic acid does not result in bacterial resistance to
antibiotics, reduction in sebum production, photosen-
sitivity (easy sunburn), staining of skin or clothing, or
bleaching of normal skin or clothing; however, 20% aze-
laic acid can be a skin irritant.
Azelaic acid is diprotic, having two pKa values. It is
quite interesting, because its second pKa is almost equal
to the pH of the skin (5.5).
We can easily understand that azelaic acid used for
any buffer.
In vitro, azelaic acid works as a scavenger (captor) of
free radicals and inhibits a number of oxidoreductase
sible of turning testosterone into dihydrotestosterone. It
normalizes keratinization and leads to a reduction in the
content of free oily acids in lipids on the skin surface.
Apart from that, azelaic acid has antiviral and antimi-
totic properties. Finally, it can also act as an antiprolif-
erant and a cytotoxin via the blockage of mitochondrial
respiration and DNA synthesis.
Beta Hydroxy Acid Peels With pKa Around 3
It is becoming common for beta hydroxy acid (BHA)
peels to be used instead of the stronger AHA peels due
to BHA’s ability to get deeper into the pore than AHA.
Studies show that BHA peels control oil and acne as well
as remove dead skin cells to a certain extent better than
AHAs because BHAs are more lipophilic than AHAs.
Salicylic acid (from the Latin Salix meaning: willow tree)
is a biosynthesized, organic BHA that is often used. Sodium
salicylate is converted by treating sodium phenolate (the
sodium salt of phenol) with carbon dioxide at high pressure
and temperature. Acidification of the product with sulfuric
acid gives salicylic acid. Alternatively, it can be prepared by
the hydrolysis of aspirin (acetylsalicylic acid) or oil of win-
tergreen (methyl salicylate) with a strong acid or base.
Salicylic Acid (pKa = 2.97)
The most commonly used peeling currently is 30% sali-
cylic acid in ethanol.
 CHAPTER 1 The Chemistry of Peels: A Hypothesis of Mechanism of Action
Salicylic acid is lipid soluble (lipophilic); therefore
it is a good peeling agent for comedonal acne. Salicylic
acid is able to penetrate the comedones better than other
acids. The antiinflammatory and anesthetic effects of the
salicylate result in a decrease in the amount of erythema
and discomfort that generally is associated with chem-
ical peels.
Salicylic acid is a key ingredient in many skin care
products for the treatment of acne, psoriasis, calluses,
corns, keratosis pilaris, and warts. It works as both a
keratolytic and comedolytic agent by causing the cells
of the epidermis to shed more readily, opening clogged
pores and killing bacteria within, preventing pores from
clogging up again by constricting pore diameter, and
stimulating new cell growth. Because of its effect on skin
cells, salicylic acid is used in several shampoos to treat
dandruff. Use of high concentrations of salicylic acid
may cause hyperpigmentation in patients with uncon-
ditioned skin, those with darker skin types (Fitzpatrick
phototypes IV, V, VI), and in patients who do not regu-
larly use a broad-spectrum sunblock.
Also known as 2-hydroxybenzoic acid, it is a crys-
talline carboxylic acid and classified as a BHA. Salicylic
acid is slightly soluble in water but very soluble in eth-
anol and ether (like phenol and resorcinol). It is made
from sodium phenolate, and this explains its direct rela-
tionship with phenol, with which it shares certain toxic
properties that become apparent when used in great
quantity and on large surface areas.
Salicylic acid is found naturally in certain plants (Spi-
raea ulmaria, Andromeda leschenaultii), particularly fruits.
Jessner’s Peel
Jessner’s peel solution, formerly known as the Coombe’s
formula, was pioneered by Max Jessner, a dermatologist.
Jessner combined 14% salicylic acid, 14% lactic acid, and
14% resorcinol in an ethanol base. Its main effect is to break
intracellular bridges between keratinocytes, whereas the sal-
icylic acid component also allows better penetration across
sebum-rich skin. It is a stronger peel than 30% salicylic acid.
Retinoic Acid Peels
CH3 CH3 O (isotretinoin; used both orally and topically), and retinal-
H3C CH3
OH
CH3
15
Retinoic acid or vitamin A acid is not soluble in water
but is soluble in fat; therefore retinyl palmitate or vita-
min A palmitate is the elected retinoic agent for chem-
ical peels.
O
O
Retinyl palmitate, or vitamin A palmitate, is the
ester of retinol and palmitic acid. Tretinoin is the acid
form of vitamin A and so also known as all-trans reti-
noic acid (ATRA). It is a drug commonly used to treat
acne vulgaris and keratosis pilaris. Tretinoin is the
best-studied retinoid in the treatment of photoaging. It
is used as a component of many commercial products
that are advertised as being able to slow skin aging or
improve wrinkles.
The terpene family, to which retinoic acid belongs,
includes numerous compounds whose common fea-
ture is that they are formed by a chain of isoprene units
CH2=C(CH3)–CH=CH2. Terpenes have a raw formula
type (C5Hx)n, x being dependent on the amount of
unsaturation. Their names depend on n:
• n = 2 æ C10: monoterpenes
• n = 3 æ C15: sesquiterpenes
• n = 4 æ C20: diterpenes
• n ≈ 1000: polyterpenes (rubber).
The main representative of the family of diterpenes is
vitamin A or retinol. Retinol is present in food (beta car-
otene) and converts completely in the skin into retinalde-
hyde (retinal). Subsequently, 95% of this is converted into
retinyl ester and 5% into all-trans and 9-cis retinoic acids.
Retinoids have multiple properties in embryogenesis,
growth control and differentiation of adult tissues, repro-
duction, and sight. In dermatology their use is well estab-
lished for psoriasis, hereditary disorders of keratinization,
acne, and skin aging. The most commonly used retinoids
are ATRA (tretinoin; used topically), 13-cis retinoic acid
dehyde/retinal and retinol (both of which are used topi-
cally). In addition, there are the synthetic retinoids such
as etretinate, acitretin, adapalene, and tazarotene.
Only the natural retinoids are of relevance in chem-
ical peelings: retinol, ATRA, and retinoic acid, the last
16 PART 1 Introductory Chapters

two of which are useful in strong concentrations as peel-

ing agents used under medical supervision.

SUBSTANCE WITH MAINLY CAUSTIC

ACTIVITY
Trichloroacetic Acid Peels
Trichloroacetic Acid (TCA) (pKa = 0.54)
O
CI

CI OH

CI

UN 1839 is required to transport it because of its corro-

sive activity.
TCA is also called trichloroethanoic acid. It is
obtained through distillation of the product from nitric
acid steam on chloral acid. It is found as anhydrous
(very hygroscopic), white crystals.
TCA can be found directly in the environment because
it is used as a herbicide (as sodium salt) and indirectly as
a metabolite derived from chlorination reactions for water
treatment. At the same time, it is a major metabolite of per-
chloroethylene (PCE), which is used mainly in the field of
dry cleaning. Its general toxicity when taken in low dose
is almost nonexistent. Its molecular structure is very close
to glycolic acid. The carbon in the alpha position has a
hydroxyl group and two hydrogens in the case of glycolic
acid, as opposed to three chlorines in TCA. TCA is a much
stronger acid than any other current acids used for peelings;
its pKa is the lowest of any current acids used for chemical
peels. Like glycolic acid, TCA does not have general toxic-
ity, even when applied in concentrated form on the skin.
When applied to the skin, it is not transported into
the blood circulation. TCA’s destructive activity is a con-
sequence of its acidity in aqueous solutions, but in peels
the acid is rapidly “neutralized” as it progresses through
the different skin layers, leading to a coagulation of skin
proteins (Fig. 1.3). As the proteins become coagulated,
the TCA is used up. To penetrate deeper, more TCA
must be applied (volume) or a higher concentration of
TCA needs to be used. TCA action is simple, reproduc-
ible, and proportional to the concentration and to the
amount applied. Unique to TCA and phenol, visual signs
(light speckling to white frost) in the skin following
application indicate the degree of coagulation of protein
molecules and the depth of penetration of the acid.
Fig. 1.3 The schematic shows the difference of skin reactivity
to the coating with TCA. The darker the area, the higher the
number of coats to be applied at the same concentration to
achieve the same level of frosting.
TCA is used as an intermediate to deep peeling agent
in concentrations ranging from 20% to 50%. Depth of
penetration is increased as concentration increases, with
50% TCA penetrating into the reticular dermis.
The quality of manufacture of a particular TCA
depends of 14 parameters linked to the raw material
itself and one parameter linked to the manufacturer
(material of protection if necessary like dust mask, eye
shield, face shield, full face particle respirator, gloves,
respirator cartridge, respirator filter):
1. The density of the vapor. Example: Relative vapor
density (air = 1): 5.6.
2. The grade of purity.
3. The quality (analytical specification of the pH).
4. The index of refraction.
5. The temperature of ebullition per liter.
6. The density in g/ml at 25°C.
7. If present, the residual traces of anions and/or cations
may cause tattooing due to increased penetration
 CHAPTER 1 The Chemistry of Peels: A Hypothesis of Mechanism of Action
depth correlative to pH. For this reason, we do not
recommend using buffered TCA or neutralizing
with plain water, which contains metallic ions. We
prefer to use TCA prepared unbuffered, completed
with bidistilled water and rose oil mosqueta.
8. Other residual chemical elements (such as SO4):
whether they should be considered as ignored.
9. The flash point (high flash point offers greater
safety).
10. The impurities if they exist—for example, nonsolu-
ble material.
11. The solubility in water in mole at 20°C, with the
clearness or colorlessness (without any color) of the
obtained solution.
12. The turbidity.
13. The pressure of the vapor (for low vapor pressure
sealing and lubrication in high vacuum applica-
tions). Example: Vapor pressure, Pa at 51°C: 133.
14. Designed for use in electrophoresis, suitable as a
fixing solution (designed for use in IEF and PAGE
gels), ≥99%. Isoelectric focusing (IEF) separates
proteins on the basis of their isoelectric point.
TCA peel solution must be stored separately from
food and foodstuffs; it should be stored in a secure cool,
dry area in a well-ventilated room. The packaging must
be unbreakable; if it is breakable, it should be transferred
to a closed unbreakable container. It is preferable to keep
TCA peel solutions in opaque glass bottles.
In addition to this detailed chemistry data, clinical
scenarios are helpful to highlight the action of TCA on
the skin. TCA is the most aggressive acid (lowest pKa of
all acids used for peels), and the depth of penetration
is correlated with its pH. The TCA application is linked
to the pressure of application, the time, the number of
coats, the total quantity used, and the neutralization.
We prefer special creams called “frosting stoppers”
instead of water to neutralize the TCA, thus avoiding
an exothermic reaction, which would provoke a “cold”
burn. In our view, unbuffered TCA prepared with pure
crystals and completed with bidistilled water with
rose oil mosqueta is less likely to provoke pigmentary
rebound or postinflammatory hyperpigmentation ver-
sus buffered TCA. It is recommended not to use water or
primary or secondary alcohols before or after the appli-
cation of an unbuffered TCA to prevent an exothermic
reaction as a reversible reaction of esterification.
Some authors mix TCA and phenol for the com-
fort of the patient, arguing that phenol helps reduce
17
the burning sensation of TCA. In fact, phenol has an
anesthetic effect. Some combinations are TCA 35% w/w
(weight/weight) and phenol without croton oil 15% to
25% w/w. However, the following must be kept in mind:
1. Both phenol and TCA are caustic, and adding both of
them will not reduce the toxicity.
2. Phenol can be diluted into TCA or vice versa to
reduce the concentration of the phenol and/or TCA.
All calculations have to be made in w/w and never in
v/v (volume/volume), because only mass are additive.
Why add another toxic substance to get a lower
concentration of TCA or phenol for peels? It is safer to
choose a lower concentration of TCA or phenol for the
peel. Furthermore, the main caustic effect of phenol is
due to croton oil and not the phenol itself.
SUBSTANCES WITH MAINLY TOXIC
ACTIVITY
Phenol ((pKaphoh2+/phoh) – 6.4 (pKaphoh/
pho−) 9.95)
Phenol is also named phenic acid, or hydroxybenzene.
It is a colorless, crystalline solid that melts at 41°C and
boils at 182°C, is soluble in ethanol and ether, and is
sometimes soluble in water.
Alcohols are organic compounds that have a func-
tional hydroxyl group attached to a carbon atom of an
alkyl chain. Benzene hydroxyl derivatives and aromatic
hydrocarbons are called phenols, and the hydroxyl
group is directly attached to a carbon atom in the ben-
zene ring. In this case, phenol is an alcohol but not
an alkyl alcohol: the group C6H5– is named phenyl,
but the C6H5OH compound is called phenol and not
phenylic alcohol.
Phenol is an aromatic alcohol with the properties
of a weak acid (it has a labile H, which accounts for its
acid character). Its three-dimensional structure tends to
retain the H+ ion from the hydroxyl group through a
so-called mesomeric effect. It is sometimes called car-
bolic acid when in water solution. It reacts with strong
bases to form the salts called phenolates. Its pKa is high,
at 9.95. Phenol has antiseptic, antifungal, and anesthetic
pharmacological properties.
Carbolic acid is more acidic than phenol, and there are
three differences between phenol and carbolic acid:
1. The aromatic ring allows resonance stabilization
of the phenoxide anion. In this way, the negative
charge on oxygen is shared by the orthocarbon and
18 PART 1 Introductory Chapters
paracarbon atoms. That is why carbolic acid is used
instead of phenol for endopeel techniques (which
lead to medical liftings obtained by chemical myo-
plasty, myopexy, and myotension).
2. Increased acidity is the result of orbital overlap between
the oxygen’s lone pairs and the aromatic system.
3. The dominant effect is the induction from the sp2
hybridized carbons; the comparatively more pow-
erful inductive withdrawal of electron density that
is provided by the sp2 system compared with an sp3
system allows for great stabilization of the oxyanion.
Resorcinol (pKa = 11.27)
HO
Resorcinol is a phenol substituted by a hydroxyl in posi-
tion meta. Hydroquinone is a phenol substituted by a
hydroxyl in position para; pyrocatechol is a phenol sub-
stituted by a hydroxyl in position ortho.
Resorcinol is also named resorcin, m-dihydroxyben-
zene, 1,3-dihydroxybenzene, or benzenediol-1,3. It is a
crystalline powder that melts at 111°C, boils at 281°C,
and is soluble.
Like phenol, resorcinol is a protoplasmic poison
that works through enzymatic inactivation and protein
denaturation with production of insoluble proteins.
Apart from that, both phenol and resorcinol act on the
cellular membrane, modifying its selective permeability
by changing its physical properties. This change in per-
meability then leads to cell death.
Phenol alone is a more powerful poison, with a sec-
ondary anesthetic effect due to inhibition of sensory
nerve endings.
Phenol and (to a lesser extent) resorcinol are cardiac,
renal, and hepatic toxins that are eliminated from the
body at 80% concentration either unchanged or conju-
gated with glucuronic or sulfuric acid.
HOW THE MOST COMMONLY
USED SUBSTANCES IN CHEMICAL
PEELS WORK: A PROPOSAL FOR
CLASSIFICATION
When making reference, even superficially, to the
chemical and pharmacological properties of these
diverse molecules, we realize that acidity is far from
being the only mechanism of action that causes the
previously documented peel-induced modifications of
the skin. The pH alone is only destructive in the case of
trichloroacetic acid. The other substances act mainly
through toxic effects (phenol, resorcinol, less so- sali-
cylic acid) or through metabolic effects in the case of
AHAs and azelaic and retinoic acids and by interfering
with cell structure and synthesis without destroying
them, but merely modifying or stimulating them.
Thus we can propose to classify the substances used
in the peels into three categories: caustic, metabolic,
and toxic. Caustic effects are localized only to the areas
that come into contact with the chemical, whereas toxic
effects, although mainly localized in nature, can also
affect cells distant from where the chemical has been
applied.
Classification of Substances Used for
Chemical Peels (L. Dewandre)
• C  austic: trichloroacetic acid
• Metabolic: AHAs, azelaic acid, retinoic acid
• Toxic: phenol, resorcinol, salicylic acid
When acidity is not the main mechanism of
action, the pH seems to be the factor that allows cer-
tain other substances present in the solution (that
have mainly metabolic effects) to penetrate the skin.
The skin and its constituent molecules, and water,
act as a kind of buffer for the solution that makes
contact and penetrates until it reaches the depth
necessary for its relative neutralization. It acts as a
blotter of the solution applied, which is more or less
avid depending on the pH and, most of all, on the
pH gradient between this solution and the depth of
the skin involved.
Toxins, particularly phenol, have little if any caustic
action (unless solutions are used that contain croton
oil); phenol solutions have a pH of 5 or 6.
We understand that there is an interest in using
peeling mixtures of different substances to minimize
complications and to take advantage of the various
mechanisms of action (caustic, toxic, and metabolic
effects). This explains the interest in Jessner’s solution
(a mixture of resorcinol, lactic acid, and salicylic acid);
Monheit’s formula (a version of a modified Jessner’s
solution with the resorcinol replaced with citric acid)
followed by the application of a TCA peel; other “secret”
modified phenol formulas; and others (Fintsi, Kako-
wicz, De Rossi Fattaccioli, etc.).
 CHAPTER 1 The Chemistry of Peels: A Hypothesis of Mechanism of Action
Fig. 1.4 The molecular structure of tranexamic acid.
The classification of A. Tenenbaum makes it easy to
understand how even some acids with pKa >3 such as
tartaric, mandelic, salicylic, and of course phenol may
not be appropriate in the hands of novice peelers.
Therefore it is recommended that beginners start by
using low concentrations of the nonaromatic diprotic or
tripotic AHAs with pKa >3.
Tranexamic Acid (pKa = 4.3) and Aromatic
Carboxylic Acid
The Role of Tranexamic Acid in Chemical Peels
Proposed mechanisms of action. Tranexamic acid
(trans-4-aminomethyl cyclohexane carboxylic acid;
TXA) has a chemical composition as shown in Fig. 1.4.
This agent was first introduced to the medical literature
in 1962 by a Japanese husband-and-wife team and was
first prescribed for heavy menstrual bleeding and dental
extraction bleeding. It is a well-known plasmin inhibitor
and is a synthetic derivative of the amino acid lysine. Its
antifibrinolytic effects occur via the reversible blockade
of lysine-binding sites on plasminogen molecules.
The figures show the molecular structure of TXA (see
Fig. 1.4) and its inhibitory role in the plasminogen cas-
cade (Fig. 1.5). Plasmin formation is inhibited by TXA,
resulting in plasmin downregulation and inability to
cleave the fibrin clot.
The effects of TXA on melanin production has been
documented in the literature; however, the biochemical
pathways and mechanisms of action are less well known.
Studies on guinea pigs have demonstrated that TXA can
reduce skin pigmentation. The mechanism of action is
not by affecting the absolute numbers of melanocytes,
but by decreasing the melanogenic activity of the mela-
nocytes, resulting in a reduced synthesis of melanin.1
Plasminogen activity is also affected by TXA. Plasmino-
gen exists in basal cell keratinocytes, and studies have con-
firmed that ultraviolet (UV) light stimulates plasminogen
19
activation, and the resultant plasmin stimulates α-MSH
(melanocyte-stimulating hormone), and therefore mela-
nogenesis.2 TXA has been found to act on UV-irradiated
keratinocytes by reducing plasmin activity in these cells.
As a result, factors promoting melanogenesis, such as
prostaglandins, are downregulated and suppressed.3,4
Another proposed mode of activity is that TXA, hav-
ing a similar molecular structure to tyrosine, functions as
a competitive inhibitor to the enzyme tyrosinase, which
is responsible for melanin production. This ultimately
results in lowered melanin production.5 A 2017 histolog-
ical analysis of melasma patients treated with oral TXA
revealed that not only was pigmentation decreased, but
patients also experienced a decrease in associated facial
erythema due to decreased vascularity and capillary
numbers and a decrease in mast cell numbers.6
Based on current histochemical studies, TXA has
been shown to have multiple effects on the skin and
exhibits the following effects on cells within both the
dermis and epidermis:
Dermis
•  Fibroblasts irradiated by UVA demonstrate an
increased expression of matrix metalloprotease 1
(MMP-1), an enzyme known to degrade collagen.
MMP-1 activity is dependent upon plasmin activa-
tion. In tissue samples exposed to UVA radiation,
TXA was found to decrease MMP-1 expression and
as a result collagen degradation. It is proposed that
TXA may confer antiaging benefits to UV-damaged
skin via a decrease in collagen breakdown.7
•  Capillary formation is suppressed by the action
of TXA. Plasmin activates VEGF, an activator of
neocapillary genesis. TXA has also been shown
to suppress basic fibroblast growth factor (bFGF),
which stimulates angiogenesis and repopulates the
microvasculature. The antiplasmin effects of TXA
therefore have shown clinical benefits by reducing
the overall blood vessel count and reducing ery-
thema.6,8
Epidermis
• TXA functions as a barrier membrane. In the epider-
mis, animal studies have demonstrated that TXA can
improve xerosis, reduce transepidermal water loss
(TEWL), and reduce inflammation by decreasing
mast cell proliferation.9
• Another in vitro study supported the role of TXA
in improving barrier function recovery because it
showed an increase in upregulation of the protein
occludin in cells treated with TXA.5
20 PART 1 Introductory Chapters

ACTIONS OF TXA ON THE SKIN

EPIDERMIS

TXA upregulates occludin, a tight

TXA blocks the conversion of junction protein and improves
plasminogen to plasmin and the barrier membrane function.
resulting cascade formation of Inflammatory mediators promote
inflammatory and melanogenic melanogenesis.
mediators.
Arachidonic
TXA reduces melanogenesis by
α -MSH
Acid (AA) down-regulation of inflammation &
possible direct competitive inhibition
FIBRIN
of tyrosinase.
DEGRADTION
PLASMINOGEN PLASMIN PRODUCTS &
INFLAMMATORY
MEDIATORS

MMP-1 VEGF &

bFGF
PLASMINOGEN
ACTIVATOR (PA)
(blocked by TXA)

Plasmin also activated by UV light,

contraceptives, pregnancy, ENO-1
cytoplasmic enzyme (higher in patients
with atopic dermatitis, impaired
keratinocyte tight-junctions, and
impaired barrier membrane function)

DERMIS
Effects of MMP-1. VEGF
& bFGF on the dermis
FIBROBLASTS
MMP-1 activated by plasmin induced kinases and results in collagen degradation.
TXA decreases MMP-1 via anti-plasmin action. This results in protection from
collagen degradation
MAST CELL PRODUCTION
VEGF & bFGF result in tryptase release and activation of destruvtive MMP-1
within mast cells. This results in basement membrane destruction.
TXA surpresses tryptase release from mast cells, reduces mast cell numbers,
reduces MMP-1, reduces inflammation, and stimulates neocollagenesis.

CAPILLARIES
Stimulated by plasmin induced VEGF & bFGF. This results in
neo-vascularisation which can result in telangiectasia.
TXA decreases VEGF & bFBF via anti-plasmin pathway &
downregulates neo-vascularisation (beneficial to melasma patients).

Proposed actions of TXA on the skin

Fig. 1.5 Actions of tranexamic acid on the skin.

• T
 XA affects keratinocytes. Enolase-1 (ENO-1) is a ubiq-
uitous cellular enzyme present both intracellularly and
on the cell surface. It is a cell surface receptor for plas-
minogen. Patients with atopic dermatitis demonstrate
increased levels of ENO-1 and plasminogen within
the keratinocytes and basal layer. Upon treatment with
TXA, it was found that in vitro tissue samples showed
reversal of tight junction protein disruption. This
implies that treatment with TXA improves the integrity
of keratinocytes within the basement membrane.10
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 Then was the time for General Pavia’s action. Arthur Houghton,
correspondent to The Times at Madrid, gives, in his “French History
of the Restoration of the Bourbons,” the account of this coup in the
General’s own words; for, favoured by the soldiers’ friendship, Mr.
Houghton had the opportunity of hearing the story first-hand, and the
smart General, looking spruce and trim in his well-cut black frock,
would often talk to the Englishman, when he met him in the salons of
Madrid, of the way he took matters into his own hand when the
republican Parliament could not manage the Congress.
“No, no,” said the former Governor of Madrid, “I admitted nobody
into my counsel, but, under the stress of circumstances, I took all the
responsibility upon myself. When I heard how the Assembly had
given voice to a vote of want of confidence in Castelar, I thought the
hour had come; and as the session the next day increased in force
and disorder, whilst the hours of early dawn succeeded those of the
evening and the night in fruitless and violent discussion, I called a
company of the Civil Guard, and another of the Cazadores, and, to
their surprise, I led them to the square in front of the Congress, and
stationed them all round the building. Then, entering the Parliament
with a few picked men, I surprised the deputies by ordering them to
leave the House. A few shots were fired in the corridor on those who
sought to defy the military order, so the members did not long resist,
and by four o’clock in the morning I found myself in complete
command of the House. I called a Committee, with the power to form
a Ministry, of which General Serrano was once more elected
President, and thus ensued the second period of the republic.”
This brilliant and successful coup reminds one of that of our
Oliver Cromwell when he freed the country of a particular
Government; but in this case of military sway in Spain General Pavia
acted from no aims of self-interest, but only for the restoration of
order, which it was his duty as Governor of the city to preserve.
 During the second period of the republic, which lasted from
January 4, 1874, till December 30 of the same year, Serrano had his
hands weighted with two civil wars—the never-ceasing one of
Carlism in the Peninsula, as well as that of Cuba—and, as Francisco
Paréja de Alarcon says, in the criticism which he publishes in the
above-mentioned work on this period, the Government formed under
Serrano proved unable to restore order and save Spain from the
dishonour which was threatening it.
So when the Ministers heard of the rising at Sagunto, on
December 29, 1874, for the restoration of the monarchy, they knew
that the movement was really supported by leading military men,
who had been inspired thereto by the ladies of the land, who
resented the irreligion and disorder of the republic; and, as they saw
that resistance would only lead to another disastrous civil war, they
resigned their posts peacefully.
It was thus that the son of Isabella II. was raised to the throne.
And Alarcon says: “The hypocritical banner of ‘the country’s honour’
was set aside; for had it not meant the support of a foreign
monarchy, destitute of prestige; and then an unbridled, antisocial,
impious, and anarchical republic, which was a blot on the history of
our unhappy Spain in these latter days, which have been so full of
misfortunes under the government of the ambitious parties which
harrowed and exploited under different names and banners?”
The Circulo Hispano Ultramarino in Barcelona, agitating
continually for the restoration of Alfonso XII., was a strong agent in
the monarchical movement. Figuerola Ferretti worked strenuously as
secretary of the society, and this officer is the possessor of the only
escutcheon signed by Alfonso XII., in which he paid tribute to the
Colonel’s valiant conduct in the Cuban War of 1872.
It is interesting to see that the opinion of the republic published in
“Contemporaneous Truths” by this Ferretti was echoed by the great
leader of the party himself, for Señor Castelar writes: “There were
days during that summer of 1874 in which our Spain seemed
completely ruined. The idea of legality was so lost that anybody
could assume power, and notify the fact to the Cortes, and those
whose office it was to make and keep the laws were in a perpetual
ferment against them.
“It was no question then, as before, of one Ministry replacing
another, nor one form of government substituting another; but a
country was divided into a thousand parts, like the Kalifat of Cordova
after its fall, and the provinces were inundated by the most out-of-
the-way ideas and principles.”
When the great republican speaks in such a derogatory way of
the republic of which he was the leader, it is not strange that public
opinion turned to the restoration of the Bourbons as the salvation of
the country. Society clamoured for such balls and entertainments as
had formerly taken place at Court, or which had been patronized by
the palace, and the dreary disorder wearied both politicians and
patriots.
The house of the Dukes of Heredia-Spinola never ceased to be
the scene of the reunion of Alfonsists, and as General Martinez
Campos played his daily game of tresillo at their table, many
expressions of hope for the return of the ex-Queen’s son fell upon
his ears; whilst the Countess of Tacon, who had been Lady-in-
Waiting to the little Prince of Asturias as a child, was loud in her
opinions. It is interesting to note that this lady subsequently filled the
same office for the restored King’s little daughter, the Princess of
Asturias, Doña Maria de las Mercedes.
From a social point of view the salon of the old Countess of
Montijo ranked foremost in Madrid, and it assembled within its walls
the frequenters of Court society in the reign of Isabella. Scenes from
“Don Quixote” were given with great success at the Countess’s little
theatre; and the year of the restoration was marked by a very
successful dramatic representation, in which some of the members
of the old nobility took part.
Moreover, the services held every Friday in the private chapel of
the mansion, where great preachers made remarkable orations,
were a protest against the irreligion of the period. On these
occasions ladies of Court society, among whom may be noted Clara
Hunt, wife of one of the diplomats of the English Embassy—who was
quite a notable singer—gave proofs of their talent.
The niece of the Count of Nava de Tajo was another of the
distinguished ladies who frequented the salon of the Countess of
Montijo. The Count was varied in his interests. One afternoon he
paid a series of visits, beginning with the Pope’s Nuncio, going on to
the house of Canovas, then to Roque Barcia, who was asking for
subscriptions for his famous dictionary, and ending with the unhappy
Lopez Bago, who was seeking support for his Review of the Salons,
of which only three or four numbers were ever published.
 CHAPTER XV
THE REVIVAL OF COURT LIFE IN SPAIN UNDER ALFONSO XII.

1874–1884

The foregoing brief sketch of the political and social life in Spain
during the republic will have given some idea of the joy which filled
Spanish hearts at seeing the Bourbons once more on the throne of
Spain in the person of Alfonso XII. Madrid indeed was wild with joy
when the little Prince whom we saw at eleven years of age, in his
blue velvet suit and lace collar, leaving his country as an exile, with
his mother and family, re-entered the royal palace as a young man
eighteen years old in January, 1875, having wisely passed through
Catalonia, which Martinez Campos had gained over to the cause,
and pleased the people by saying: “I wish to be King of all
Spaniards.”
As Isabella had abdicated in favour of her son on June 26, 1870,
there was no impediment to his taking the oath of coronation soon
after he was summoned to the Spanish capital. Of a good figure,
gentlemanly, and well cultured, Alfonso added the art of good
dressing to his other attractions, and the excellent taste and cut of
his clothes led to his being called “the Beau Brummell of Spain.”
 K I N G A L F O N S O X I I . V I S I T I N G C H O L E R A PAT I E N T S AT
ARANJUEZ

From a Painting by J. Bermudo y Mateos

The Countess of Campo Alange, who had assisted at the

ceremony, in Paris, of Isabella’s abdication in favour of her son, was
one of the first to pay her respects to Alfonso XII. on his return as
King to the Court of Spain. She went in a beautiful costume of
crushed-strawberry-coloured satin, and she carried in her hand a
snuff-box decorated with a picture of the entry of Charles IV. into
Badajoz, and it was with a graceful speech that the Countess drew
the King’s attention to the miniature.
“What a memory you have, Marchioness!”
“Oh, facts and people remain in my mind when they are forgotten
by others,” returned the lady; and the affectionate look she cast at
the King reminded him of her fidelity to his family.
 In his youthful exuberance of spirits, the young King was always
ready to join in any frolic, although he was not lacking in serious and
intelligent application to matters of State.
It was the Monday preceding Shrove Tuesday, and Alfonso had
remarked somewhat regretfully that the rollicking spirit of the season
seemed somewhat subdued. This the Duke of Tamanes determined
to remedy, so, when the Cabinet was assembling for a royal
audience, he swiftly emptied a bag of flour over the head of the
Minister of War, who gravely sat down to business in his transformed
condition, much to the amusement of Alfonso.
The young King was always genial and affable, and anxious to
avoid too much ceremonial etiquette when it might cause discomfort
to those who followed it.
One day he came unexpectedly into the Archæological Museum
of Madrid with an Austrian Prince. There he found two men studying
with their hats on; for all those who use public institutions in Madrid
know that the cold is intense during the winter in these buildings. At
the entrance of Alfonso the students promptly bared their heads.
“Don’t do that,” said the young King kindly; “put your hats on
again, or I shall have to take off mine.”
Alfonso was a bright and attractive figure in Spanish Court
society. His gift of making verses, either gay or sentimental, as the
occasion warranted, was always attractive, and he slackened the
stiff rules of Court life as much as possible.
The Ilustracion Española y Americana publishes an excellent
account of the historic ball given by the restored monarch:
“The festivities which celebrated the restoration of King Alfonso
XII. in the feudal mansions of Spain finally saw their culmination in
the magnificent ball given at the royal palace by the young monarch
and his widowed sister, the Infanta Isabella, the heir to the throne, on
January 15, 1877.
“The state apartments were illuminated by millions of candles in
the crystal chandeliers; the double-winged splendid staircase—
guarded at the foot by the historic white marble lions, and lined with
the Royal Guard of the Halberdiers in their high black-cloth leggings,
slashed scarlet cutaway coats, tricorn white-banded hats, and their
glittering Toledan steel halberds, at attention—was crowded with
thousands of guests in gorgeous uniforms and lovely toilettes, who
were radiant at this opportunity of once more greeting royalty at a
great fête.
“The King, with his sister, looked smiling and happy, and their
genial words of welcome warmed the hearts of the guests.
“The fine ballroom was soon filled with the stream of people in
gorgeous array; the large mirrors on the wall reflected the dancing of
the stately rigodons, so that they could be seen from the entrance of
the room even by those who could not obtain a place within its
precincts.
“A magnificent supper was served, and so perfect was the
arrangement that 3,000 people were able to partake of it without
confusion.
“To the royalties who gave this ball it offered little real enjoyment,
for the strict Court etiquette only allowed them to dance a few
rigodons according to the protocol, and to pass through some of the
illuminated salons, where they greeted those privileged to approach
them.”
In his anxiety to make acquaintance with his kingdom, Alfonso
went this year to Barcelona, Granada, Malaga, Seville, Asturias,
Galicia, etc., and he took his place as the head of the grandees of
Spain when, with all due pomp and ceremony, he was made Grand
Master of the Orders of Santiago, Alcantara, Calatrava, and
Montesa.
It was on December 8 in this year that the Duke of Sexto went to
Seville to formally ask for the hand of Doña Maria Mercedes, the
seventeen-year-old daughter of the Duke and Duchess of
Montpensier, in marriage for her cousin Alfonso XII.
The royal suitor had long been attracted to this charming girl, and
during the years of his exile many were the happy days he spent
with his cousin in his vacations from Sandhurst at Vichy. When
walking out together in the watering-place, the thoughts of the young
people would sometimes wander to the possible future, and the
young cadet, whose purse was occasionally very attenuated, would
regretfully turn away from some pretty present he would gladly have
bought for his cousin, saying: “It is rather dear; but never mind, I will
buy it when I am King.”
The account of the delicate mission of the Duke of Sexto, the
Marquis de la Frontera, the Chamberlain, and Don Fernando
Mendoza, Secretary of the Etiquette and Mayordomo of the Royal
Palace, is given in the publication mentioned below.[20] The Duke
and Duchess of Montpensier were in the white salon of their palace
when they received the request for the hand of their daughter in
marriage to the reigning King of Spain; and they were well pleased
with the suggested alliance, as they trusted that the hope of Louis
Philippe, that his descendant should sit upon the throne of Spain,
would soon now be fulfilled.
[20] “The Wooing and Marriage of Alfonso XII.”

When Alfonso followed the favourable reception of his request by

a visit to Seville, all went merrily enough in the royal circle.
A magnificent Court ball was given at the Palace of San Telmo on
December 26, to celebrate the royal engagement. The first rigodon
was led off by the King with his fiancée, looking fascinating, gowned
in white and glistening with jewels; the Infanta Doña Luisa Fernanda
danced with the Duke of Sexto, and Alfonso excited much admiration
by the able way he conducted the cotillon.
However, the Princess of Mercedes had not been the only girl
friend young Alfonso had had during his exile. For when he could not
go to the Montpensiers at Vichy, the ex-King liked to visit the Austrian
Archduke and Duchess at Biarritz, as he found their daughter Maria
Cristina très bonne camarade, and well able to hold her own with
him in a game of tennis or billiards. Maria Cristina seems to have
been attracted by Alfonso, for when his marriage was announced
with Mercedes of Montpensier, she joined the rich and noble Chapter
of Prague, of which she accepted the responsible office of Lady
Abbess, with an annual income of 20,000 marks.
The marriage of Mercedes and Alfonso took place on January 23
with all befitting ceremony. The Patriarch of the Indias blessed the
union in the Church of Atocha. The ex-King Francisco was best man,
and the Infanta Isabella represented her grandmother, Queen Maria
Cristina, as the chief lady at the ceremony.
The retinue of the palace, the grandees, the fine caparisoned
horses with their bright-liveried lackeys, the gorgeous coaches with
their magnificent trappings, all made a striking show as they swept
through the Spanish capital from the church to the Court.
But a note of horror was struck when a sudden awful sound was
heard, and a woman fell dead struck by a bomb; but no other fatality
occurred, and cheers filled the air as the troops of the capital filed
before the palace, where the Royal Family witnessed the review
from the windows.
The genial character of the young King was seen in a letter to an
Archduke, a college friend, shortly before the death of his beloved
Mercedes. This friend, with all due respect to Alfonso as King,
mentioned the fact of his marriage with a young Princess of Spain.
To this communication the King replied that he never forgot college
friends, whom he preferred in many cases to later ones.
“I forbid you to address me as ‘Majesty’; treat me as you treated
me in the Teresiano. When you marry, come to Madrid with your
wife, whom I shall at once regard as a friend. Mercedes is very kind;
we will hunt, and we will chat about old times, and so your
honeymoon will be spent as happily as mine was....”
But a telegram soon followed this bright and happy letter. It ran
thus:

“My dear Frederick,

“Queen Mercedes is dead. May God give you in your
marriage the happiness which He has denied me! In your
approaching days of joy remember the woe of your friend.
“Alfonso.”

It may be mentioned that Queen Isabella wrote to Madrid to

signify her displeasure at her son’s marriage, for the fact that the
daughter of Montpensier, who had intrigued to succeed her on the
throne, became Queen of Spain was rather a bitter pill to swallow.
However, all animosity on that score ceased at the death of the
beautiful and lovable Queen, who had had undisputed sway in the
heart of her young husband, and whose intelligence and good
feeling at the age of eighteen had promised so much good for the
country. There were not lacking those who attributed the dreadful
event to the enemies of the Montpensiers, but others said it was due
to a chill. During the sufferings of the last few hours the young
husband sat in sorrow by the bedside, and the much-loved wife
strove between her attacks of pain to comfort him with the hope of
meeting in a future world.
At last all was over, and the poor young Queen was laid out in
state on a low couch in the stately Hall of Columns. This Hall of
Columns was often used for state banquets, but, after being the
scene of the last sad functions in honour of his beloved wife, Alfonso
had a new banqueting-hall built, and the salon of such sad memories
has never since been used for any but solemn ceremonies, such as
the washing the feet and feeding the beggars by royalty on Maunday
Thursday, the Chapter of one of the grand military Orders, etc.
The corpse of the young Queen was dressed in the white garb
and black cape of a nun of the Convent of Don Juan de Alarcon; the
lower part of her face was covered with a white gauze handkerchief;
her beautiful white hands, which looked like wax, were crossed on
her bosom; and her face, which had been so admired a few short
weeks before—when, according to the custom of Spain, she passed
through the streets on foot on Holy Thursday, to make her visits to
the churches in company with her husband and the Court—looked
drawn with pain and fever as it lay in the light of countless candles.
The public defiled sadly through the mortuary chapel, and many
were the Masses celebrated by the Church dignitaries on the altar
erected at the end of the hall.
On the day of the funeral the royal cortège solemnly passed
down the soldier-lined streets to the station. The sound of the
horses’ hoofs was deadened by the tan with which the roads were
strewn, and the silence was only broken by the piercing note of an
occasional clarion or the dull tattoo of the muffled drums. Grandees,
Gentlemen-in-Waiting, mace-bearers, and officers, all with crape
badges, preceded the catafalque, before which was borne the
standard of the Sisterhood of the Royal House, followed by the cross
and the clerics in their vestments. Finally came the band of the
halberdiers, whose soblike strains of a funeral march was in tune
with the occasion.
At last, for the first time in history, the remains of a Queen were
placed on a railway-train for the Escorial, and so the coffin of
Mercedes left the station amid the booming of the cannon and the
strains of the Royal March played for the last time in her honour.
A short time after the death of the Queen, Alfonso was the object
of a regicidal attempt as he was passing No. 93 of the Calle Mayor,
on his way from the station to the royal palace after a visit to
Asturias. The criminal was a young fellow, twenty years of age, from
Tarragona, named Juan Oliva Montcousi, and he was caught with
the pistol in his hand before he had time to discharge it. The young
King was enthusiastically acclaimed when he calmly pursued his
way home as if nothing had happened.
Alfonso’s three younger sisters, Doña Pilar, Doña Paz, and Doña
Eulalia, were often seen at this time in a quiet carriage making
excursions together, so when the news of the death of Doña Pilar
spread through the capital it gave quite a shock to Spain.
It was said that the death of the Infanta Doña Pilar was indirectly
due to a shock received during the review held in honour of the
Prince of Austria. This Prince was known to have made a favourable
impression on the Infanta, and if she had lived it would probably
have resulted in a marriage. But, unfortunately, as the artillery
carriages in the military function were passing down the Alcalá, one
blew up and killed several soldiers on the spot. Perhaps for a
moment the Infanta feared that the honoured guest was among the
killed and wounded. Be that as it may, she and other members of the
Royal Family were upset in the carriage, and she died six weeks
later.
Talk of the second marriage of the King followed very soon after
the death of Queen Mercedes, as a direct heir to the throne was so
essential to the country, and all eyes turned to Maria Cristina
Enriqueta Reniera, daughter of Charles Ferdinand, Archduke of
Austria, as the future Queen of Spain. The Duke of Bailen went to
Vienna to ask the Emperor Joseph of Austria for the hand of his
daughter, the Archduchess Maria Cristina, for his Sovereign, King
Alfonso of Spain.
On August 22 Alfonso arrived at Arcachon, incognito, under the
title of the Marquis of Covadonga, to claim in person the hand of the
Archduchess.
Alfonso had reason to expect he would be favoured by Maria
Cristina, as she had always seemed to enjoy his society when he
came to visit her family, as a young cadet from Sandhurst. The royal
wooer gave expression to his poetic feeling when he found himself
on such a delicate mission at the beautiful spot which had been so
frequented by our poet Shelley. People in the place seemed at once
to recognize the royal visitor, especially as he wore his arm in a
sling, from the effect of a carriage accident which had been noised
abroad.
Anxious for the interview which was to decide his fate, Alfonso
took a basket pony-carriage from Monaco to Arcachon, and, in
company with the Duke of Tetuan and the Spanish Ambassador from
France, he soon found himself at the Villa Bellegarde, the abode of
the Archdukes of Austria.
When the young King passed into the salon, where he was soon
welcomed by Maria Cristina, his eyes fell upon the portrait of
Mercedes, whom he had lost a few short months before, and he
soon found that his bride-elect was in sympathy with his sorrow for
his loss, for, in a voice trembling with emotion, she said:
“My dearest desire is to resemble Mercedes in all things, and
even if I am to succeed her I can never dare hope to supplant her.”
 Such a sympathetic speech could but unseal the heart of the
widowed King, and, having succeeded in his wooing, Alfonso could
hardly tear himself from the side of the young Archduchess, with
whom he could talk so freely of the wife he had lost.
On August 29 the young King finally left Arcachon; the
Archduchess accompanied him as far as Bordeaux, and the royal
marriage was fixed for November 29.
When the Archduke and Duchess and their daughter arrived at
the Casa de Campo on November 23, they were met by the King, his
three sisters, and the royal retinue, who accompanied them to the
Palace of the Pardo, where the marriage settlement was signed on
the 28th.
The bride-elect won all hearts by her delicate and sympathetic
behaviour on the occasion, for, turning to the Patriarch of the Indias,
she said, in a voice broken with feeling: “Pray that I may make the
King happy, for it is a difficult task to succeed a Queen who was a
saint, and who will always live in the affections of the King and the
people of Spain;” and here she drew a miniature of Mercedes from
her bosom, and gazed at it with respectful admiration.
This ceremony took place in the banqueting-hall of Ferdinand
VII., and, to the delight of the Spanish people, it was graced by the
presence of the ex-Queen, Isabella II.
“The great Isabella is coming!” was the cry that rang through the
capital, and the dethroned Queen was moved at the enthusiasm of
her quondam subjects as she passed through the city, for she saw
that there was more fidelity in her people of low degree than there
had been gratitude in the hearts of the great whom she had
overwhelmed with favours.
The wedding ceremony took place in the Church of Atocha, and
hardly was the service concluded when the King’s bride went and
knelt at the feet of Isabella and kissed her hand. It was a tribute of
gratitude to her royal mother-in-law, for it was a fact that the
influence of his mother had led the young King to take his new bride
from the House of Austria. Isabella had signified her disapproval of
the union with the Montpensiers by not being present at that
wedding, but this marriage she favoured from the beginning.
A few days after the royal marriage an attempt was made on the
lives of the young couple, by a man named Francisco Otero
Gonzalez, as they arrived at the chief entrance to the royal palace;
but, fortunately, although the bullet almost grazed the forehead and
neck of the King and Queen, they escaped unwounded.
Queen Maria Cristina is a very accomplished woman, and she
soon set herself to learn the language of her adopted country. In her
eagerness to master the tongue, she often turned to King Alfonso to
supply her with the word she required, and, in fun, he would often
supply her with some expression which she saw, by the looks of her
entourage, was hardly fitting for a lady. Maria Cristina proved she
had made great progress in Spanish when she was able, with all the
gracious courtesy for which she was noted, to ask of a certain
academician, who was complaining of the hatred of Sagasta, would
he not do better to use the word inquina than inquinia?
The affection with which the Queen inspired the young King was
seen in his daily letters to the Court when journeys on State
business obliged him to absent himself from Madrid.
“I have just put your carnation in water,” he would write; and the
many other allusions to their little domestic joys showed that the
heart of the King was with the Queen in his absence.
The Queen had to contend with national jealousy at Court when
she intimated her wish that her Austrian physician, Dr. Riedel, should
attend her in her forthcoming accouchement. Court etiquette was
not, however, to be set aside even by the chief lady in the land, so
the matter was finally settled by the doctors of both countries
presiding jointly over the event. Thus the little Princess of Asturias
made her entry into the world, on September 11, 1880, with her right
hand held by the Austrian physician, Dr. Riedel, and her left in the
grasp of the Court doctor of Spain.
The young King proudly presented his little daughter to the Prime
Minister and his Cabinet, the Court officials, and the military
diplomats and clerical dignitaries, assembled in the antechamber, as
she lay in a nest of costly lace on the historic silver tray.
On September 14 the baptism of the infant Princess of Asturias
was celebrated with all the pomp usual to the occasion. The galleries
were hung with the historic tapestries, representing Bible scenes.
The Royal Guard, in their classic dress and with their shining
halberds, formed a line on either side of the gallery between the
people and the royal procession.
First came the Gentlemen-in-Waiting, de casa y boca (of the
house and the mouth), their gold or silver keys signifying the
respective offices of attendance; then came four mace-bearers,
grandees of Spain, the men-at-arms with the royal arms, all the
Infantes and Infantas in full Court dress, with their ladies and
gentlemen in attendance; the seven gentlemen of the Chamber—the
Marquis of Salamanca, the Dukes of Almenara and Valencia, Count
Villanueva de Perales, the Marquis of Sotomayor, the Marquis of
Benamejis de Sistallo, and the Count of Superunda—all passed in
gorgeous dress and with stately step, bearing respectively the salt,
cut lemon, cruse of oil, piece of cotton-wool, the cake, the white
cape, and the water of Jordan, which all had their part to play in the
baptismal service.
The royal infant itself was carried between Isabel II., who was
godmother, and the Pope’s Nuncio, who represented His Holiness as
godfather. Then followed the proud young father, accompanied by
his military suite, and the procession ended with the band of the
halberdiers, playing a cheerful march from an opera. By the wish of
the Queen, the infant Princess was named, after her predecessor,
Mercedes.

D O N C A R L O S , P R I N C E O F A S T U R I A S , A N D H I S L AT E W I F E , T H E
I N FA N TA M E R C E D E S

It was in 1882 the King and Queen paid a visit to the Duke and
Duchess of Montpensier at their beautiful Palace of Sanlucar de
Barrameda, and the Queen won the hearts of her host and hostess
by her charming manners and the admiration with which she always
spoke of their daughter, the late wife of Alfonso.
On November 12, 1882, the Infanta Maria Teresa was born, and
two days later she was baptized with the customary ceremony.
On April 2, 1883, the King’s sister, Doña de la Paz, was married
very quietly to Prince Lewis Ferdinand of Bavaria. The Prince is a
very able surgeon, and when he comes to Madrid he delights in
going to the military hospital and exhibiting his scientific skill on
some soldier-patient.
The newly wedded pair laid the foundation-stone of the Cathedral
of the Almudena, and, according to the custom, the Princess de la
Paz placed in the casket a poem from her own pen to the Virgin of
the Almudena. The departure of the Infanta de la Paz left the Infanta
Eulalia with no companion in her musical and artistic tastes, for the
sisters had worked, played, painted, and poetized, together.
In September, 1883, Alfonso XII. went to France and Germany.
True to his old friends, the King went to see the Warden of the
Teresian College at his private house. As he was not at home,
Alfonso asked for a pencil and paper to write him a note, which he
handed to the servant. When she saw that the letter ran,

“I came to pay a debt of gratitude by coming to see you. I shall be

going to the Teresian College in two hours.
Alfonso, King of Spain”

she fell on her knees and entreated forgiveness for her stupidity in
having asked the royal visitor into the kitchen.
But Alfonso, with his usual kindness, expressed interest in this,
the first kitchen he had ever seen. He asked many questions about
the utensils, and showed great curiosity about the use of a ceramic
vessel, which, according to the description he subsequently gave
and the sketch he made of it to show the Court officials, proved to be
an egg-poacher.
The enthusiastic reception accorded to Alfonso at Homburg
excited the ire of the French, and so antagonistic was the exhibition
of public feeling as the young King was crossing Paris alone that he
informed the President of the Republic that he would recall his
Ambassador at once. This prompt act brought the necessary
apology, and the King of Spain subsequently attended the banquet
given in his honour at the Elysée, at which the Minister of War was
absent, as the President of France had asked him to send in his
resignation.
The news of this contretemps reached Spain, and when the
Queen returned from La Granja to Madrid she was at first quite
alarmed at the enthusiasm shown by the people at the station. She
clasped her children to her breast, and seemed to think she was on
the brink of a revolution. But her fears were soon stilled when
somebody shouted: “Señora, the Spanish people are only protesting
against the recent events in Paris.”
The return of the King from France saw an ovation of equal
enthusiasm, and, in defiance of all Court etiquette, the people
pressed up the staircases and into the galleries of the palace, crying:
“Viva el Rey y la Reina!”
It was on Maunday Thursday, 1884, that the Court went for the
last time in state to make the customary visits on foot to the chief
churches of the capital. There was the usual service in the morning
in the chapel of the palace, the washing of the beggars’ feet and
feeding them,[21] and the solemn, imposing public procession at
three o’clock in the afternoon. The streets were strewed with tan to
soften the cobbled stones to the feet of the ladies, whose high-
heeled velvet shoes rather impeded their walk. The streets were
lined with troops, and the Plazas de Oriente, Mayor, and La
Encarnacion, were respectively filled with the regiment of the
Princess of Pavia and the artillery.
[21] This ceremony is described on pp. 332-4.

First came a mounted company of the Civil Guard; then a long

line of kettle-drummers, the grooms and all the officials of the Court,
all in full dress; then the six men-at-arms with their embroidered
vestments, the Chamberlains, gentiles hombres, the grandees of
Spain, the King’s military retinue, etc.
Their Majesties walked between the lines of halberdiers, followed
by the Patriarch of the Indias, the Ministers of the Crown, the chiefs
of the palace, the Ladies-in-Waiting, and the Aides-de-Camp of the
King and Queen.
A Captain of the Guard and about thirty lackeys carried the
historic sedan-chairs, and notable among them were those of the
Dukes of Granada, Osuna, and Villahermosa, ornamented with
beautiful paintings.
The procession ended with a company of halberdiers and a
squadron of the royal escort.
Don Alfonso walked with martial step, his head in the air, and
smiling pleasantly to all the friends he saw. He was in the uniform of
Captain-General, with the Order of the Golden Fleece and other
decorations.
In this final public visit to “the Virgins,” the Queen wore a white
velvet robe embroidered with gold and ornamented with sapphire
buttons, and her necklace and bracelets were of the same precious
stones. She wore the Orders of Maria Luisa and the starred Cross of
Austria. The dress of the Infanta Isabella was of pale blue velvet
embroidered with flowers, and all the dresses and mantles of the
royal ladies were of equal magnificence, with tiaras of jewels and
feathers and mantillas on their heads, and, as all the ladies of the
Court also had their places in the procession in splendid attire, one
can imagine it was a superb show; but it was not one to be seen
again in the public streets.
The health of the King was now beginning to give anxiety at
Court, and loyal subjects regretted that people in high places did not
use their influence to stimulate the King in his good desires for the
welfare of the land, instead of pandering to his fancies with adulation
and flattery.
Charming ladies literally forced their way into the palace, and one
day Queen Maria Cristina gave a well-deserved[22] box on the ears
to the Duke of Sexto, when she came upon him introducing a dancer
of light character to His Majesty. It is noteworthy that one of the first
acts of the Queen as a widow was to ask this Duke to resign his post
at the palace.
[22] “La Vie intime d’Alfonse XII.,” par Croze.

It was to such flattering courtiers that Maria Cristina owed the

shadows which crossed the happiness of her married life, for under
good influence Alfonso would always have been true to Maria
Cristina, as the King loved and venerated her above all women; but
when politicians encouraged the escapades of an attractive young
Sovereign the wife’s influence was weakened. Queen Maria Cristina
was deeply offended when she found that her husband’s connection
with this Elena Sanz was a well-known fact, two sons being born to
the singer.
It was then that it was seen that the Queen was no mere weak
woman who would submit calmly to what might be termed los
costumbres (custom) of the Court; and when she found that the King
had a rendezvous with a señorita in the Casa de Campo, the
magnificent wide-stretching park beyond the palace, she declared
she would leave Spain and go back to Austria.
Nothing but the strong pleas and arguments of those about her,
including Alfonso XII., persuaded her to stay at the Spanish Court,
and it was certainly due to this illustrious lady that a higher morality
there became customary. For, as nobody ever was able to breathe a
word against her honour, she subsequently exercised her right, as
Queen-Regent, of sweeping the Court clean of those who smirched
its purity.
Moreover, those who had expected Alfonso XII. to save Spain by
the introduction of a pure and unmystified suffrage, such as he had
seen in England when studying at Sandhurst, were disappointed in
their hopes; for Canovas, the leader of the Conservatives, openly
said at Court: “I have come to continue the history of Spain”—which
meant the history when the voice of the people is not heard; and
Sagasta, the head of the Liberals, acted in the same spirit, although
he did not express himself so openly.
Canovas, the leader of the Conservatives, and Sagasta, the chief
of the Liberals, used all their eloquence at the Court of Spain to
persuade Alfonso XII. that sincere elections in Spain would lead to
the Carlists attaining a majority in the Congress. So the King, not
seeing that the leaders of both parties wished to prevent the
realization of a true Parliamentary representation, because it would
lose them their patronage of deputies’ seats, ended by signing the
Pacto del Pardo. This document, endorsed by the King at the
country palace, was simply an arrangement between Canovas and
Sagasta, by which each was insured an equal period as Prime
Minister, so that their respective partisans could feel that their
patrons had the same amount of influence.
 P R A X E D E S M AT E O S A G A S TA , L I B E R A L P R I M E M I N I S T E R

And yet Alfonso XII., who was overborne by what he considered

the experience of the two leaders, had the welfare of his country at
heart, for he said to Ernest Daudet: “I am Sovereign, and as long as I
am King of Spain I will never allow a Ministry to be overthrown by an
intrigue in the palace, as it has frequently happened hitherto. If the
country wants a Liberal Government, it shall have it; but, before
talking of liberty, Spain herself must have both liberty and stability. As
to those who say I am not accessible to truth, it is because they have
not tried to show it to me. The country is difficult to manage; it is
impatient, and cannot see, as I do, that its condition requires
prudence and management. We have remade the army; we have not
had a manifesto for three years. We have a standing army of 80,000
men, and we have been able to send 20,000 to Cuba. The
insurrection of Cuba is a great wound, and it must be healed before
we can cure the other evils.” But the King was never allowed to take
the sure means of healing these wounds; he was never permitted to
say: “I wish to respect the people and their votes, and by the Law of
the Universal Suffrage they can go to the polls.”
With the loss of the love of his life, the young Queen Mercedes,
Alfonso seemed to become enervated, and self-interested courtiers
found that they could use the King’s pocket for the protection of
needy ladies of all ranks.
Canovas and Sagasta were both aware of this abuse, and,
indeed, both these Ministers were themselves under the influence of
certain ladies, who used their power over these Ministers to their
own pecuniary advantage; for they themselves were liberally
rewarded for the titles which they persuaded these politicians to ask
the King to grant.
The Queen’s ignorance of Spanish when she first came to Madrid
made it more difficult to contravene the influence of the camarillas,
which wove their nets round the young husband, whose real wish for
the welfare of the country would have made him a willing disciple of
good advice.
Moreover, flattering courtiers carefully concealed from the King
the sad results which would inevitably follow his course of self-
indulgence, and the palace became a constant scene of camarillas
and intrigues which could but be disastrous to the land.
Even Nakens (whose protection of the anarchist Morral, after the
bomb tragedy of the royal marriage morn of May 30, 1906, led to his
being imprisoned for nearly two years) pays tribute to the wish of the
young King to act for the welfare of the kingdom, for, in a collection
of his articles published when he was in gaol,[23] we read an appeal
to Alfonso to consider his own good with regard to his health, and
not to listen to self-interested advisers.
[23] “Muestras de mi Estilo,” Nakens.

“Nobody,” says the writer in this appeal, “has the courage to warn
you of the impending evil. When the doctors order you change of
climate, the Government opposes the course for reasons of State.
‘Reasons of State’ imperil the life of a man! And a man to whom we
owe so much!
“Therefore, even as a republican, I beg you, as the occupier of
the throne, to look to your health, if it be only to overthrow some
iniquitous plan, or some unworthy object which is contingent on your
illness; and if scientists think it well for you to pass the winter in
some other place in Spain, or abroad, follow their counsel, and not
that of interested politicians, in sacrificing your life to their ambitions.”
It was certainly true that the King was overborne by the intrigues
of the politicians in the palace. Even in such a little social matter as
that of wishing to go in costume to a fancy ball, the King could not
have his own way, for Canovas showed such aversion to Alfonso
donning fancy attire for the occasion that he had to abandon the idea
and wear his ordinary dress.
If such influence had been used to the prevention of the King
favouring a danseuse like Elena Sanz, which brought so much
sorrow and so many complications in the Royal Family, his life might
certainly have been prolonged. It was true that the doctors advised
the King’s wintering in Andalusia, but “State reasons” led to the
failing Sovereign being exposed to the colder climate and sharp
winds of the Palace of the Pardo, where politicians could use their
influence with the invalid, and remind him continually that he alone
was the arbiter of parties.
 Alfonso was only twenty-seven years of age when he felt he was
doomed to an early death; but his natural energy led him to take
horse exercise, despatch business with his Ministers every day, and,
in spite of daily increasing weakness, to do as much as possible.
If his longing for the sea-breezes of San Sebastian had been
gratified, his life might have been prolonged; but politicians gave little
heed to the plea, and their authority was paramount.
On November 24, 1894, the royal invalid was seized with
faintness when he came in from a walk. Queen Maria Cristina,
Queen Isabella, and the Duchess of Montpensier, were called to his
side. Seeing his wife by him when he recovered consciousness, the
King embraced her, and the alarming symptoms vanished for a time;
but the following day he was seized with another fainting fit, which
proved fatal.
We read in La Ilustracion Española of this date, that when Queen
Maria Cristina was told by Dr. Riedel that all was over, she fell
weeping at the head of the bed of her unhappy husband, whilst
covering his hand with kisses.
 D E AT H O F A L F O N S O X I I .

After the Painting by J. A. Benlliure y Gil

Cardinal Benavides performed the sacred office of the occasion.

The doctor could not suppress his emotion, and hid his face, covered
with tears, in his hands; and Count Morphy, the King’s faithful
secretary, went sorrowfully to announce the sad news to the Queen-
mother and the rest of the Royal Family.
At nine o’clock the next morning the little daughters came to
embrace their father for the last time. The Queen, with only the
assistance of Dr. Camison, prepared the body of her husband for
burial, and she assisted at the obsequies in the Escorial with her little
daughter, the Queen of Spain. Arrived at the historic monastery, the
Augustine Brothers came to meet the sad cortège, in their black
vestments and holding lighted torches, and, headed by the Prior and
the Principal, the procession passed to the burial-place of the Kings.
 The iron seemed to enter the soul of Maria Cristina when the
Chief of the Palace cried before the catafalque: “Señor, señor,
señor!”
Solemn silence reigned. “Then our Sovereign really is no more,”
said the Chamberlain. He broke his wand of office, whilst the drums
of the halberdiers, the bells of the cathedral, and the booming of the
cannon, added to the solemnity of the occasion. The Bishop of
Madrid officiated at the final office, after the coffin was finally carried
with countless candles down into the Pantheon, which he had
entered ten years before in all the exuberance and with all the
illusions of youth.
Then the unhappy widowed Queen returned to Madrid, there to
pass the sad months till the child should be born who might prove
the future King of Spain.
It was an impressive sight to see the Queen, with her orphaned
little girls, take the solemn oath of Regency. Putting her hand on the
Gospels, which the President held open, she said:
“I swear by God to be faithful to the heir of the Crown during the
minority, and to guarantee the Constitution and the laws. May God
help me and be my Defence; and if I fail, may He require it of me!”
Then the Queen sat down with her little girls, and the Prime
Minister made the following formula:
“The Parliament has heard the solemn oath just made by Her
Majesty the Queen-Regent, to be faithful to the legitimate successor
of Don Alfonso XII., and to guard the Constitution and its laws.”
The marriage of the Infanta Eulalia with Don Antonio, son of the
Duke and Duchess of Montpensier, in 1886, was the next interesting
function at the Court of Spain.
The Montpensiers seized this fresh opportunity of becoming
connected with the Spanish Royal Family, and Doña Eulalia
augmented their riches by a large sum of money; but it seemed as if
fate wished to warn the Infanta that the marriage would not be
happy, for it was postponed through the illness and death of her
brother, and she was weeping as she came out of the royal chapel
on her wedding-day. And, indeed, it was not long before the Infanta
found her husband was utterly unworthy of her, and she now lives
apart from him.
The Infanta Eulalia was a great loss to the Court of Spain, where
her bright intelligence and charming ways had made her presence
like sunshine. She was twenty-two years of age when she married,
very pretty and high-spirited, an expert in riding and driving, and a
lover of all kinds of activity.
Her father, Don Francisco, and the Duke of Montpensier—who,
we know, killed Don Enrique, her uncle, in a duel—supported her at
the altar; and Queen Isabella, the Comtesse de Paris, the Queen-
Regent and her little daughters, were also at the ceremony.
This Infanta is often seen at the Court of Spain, with her son
Alfonso. It was she who warned Alfonso XIII., when he presented his
new-born son to the assembled Ministers, that the infant might catch
cold if exposed too long; and at the royal baptism on June 2, 1907,
she looked striking in her long train of scarlet velvet, with the satin
front sewn with jewels, and with scarlet plumes surmounting her tiara
of diamonds.
Even those who had not been in favour of Alfonso were rapidly
gained over to the Bourbons when they saw the difficult position of
the Queen-Regent. All the chivalry of the Spaniards was aroused to
support the young widowed mother in her trying task.
When a lady of the Court condoled one day with the royal widow,
and expressed wonder that she could so valiantly seek to steer the
ship of State whilst suffering the pain of loss, and not knowing how
fate would settle the question of the future Sovereign of Spain, Maria