Original Contributions
Tachyphylaxis to the Action of Topically
Applied Corticosteroids
Anthony du Vivier, MB, MRCP, Richard B.
Stoughton, MD
Arch Dermatol/Vol 111 , May 1975 pp.581-583
Accepted for publication Nov 21, 1974. From
the Division of Dermatology, Scripps Clinic and Research Foundation, La Jolla,
Calif. Reprint requests tc 476 Prospect St, La Jolla, CA 92037 (Dr. Stcughton).
A previously unrecognized pharmacological
event, acute tolerance to the vasoconstrictive action of topically applied
glucocorticosteroids, has been discovered in human skin. Thus, potent topical
glucocorticosteroids will cause vasoconstriction when first applied to human
skin but with subsequent applications the production of vasoconstriction
rapidly diminishes. However, after a rest period of a few days, the same
Initial vasoconstrictive effect may be produced again, but this will also
disappear if the steroid is again continued topically. These observations have
important applications to optimum timing in the clinical topical use of
glucocorticosteroids for maximum therapeutic advantage.
This article reports the occurrence of
acute tolerance to the vasoconstrictive action of topically applied
corticosteroids when administered repeatedly. This phenomenon, known as tachyphylaxis
and easily demonstrated with many drugs (including catecholamines), may give a
clue as to how topically applied corticosteroids cause vasoconstriction. Also,
it may possibly serve to explain a not-infrequent patient complaint that their
responsiveness to new corticosteroids, although often marked at first,
diminishes with constant usage.
MATERIALS AND METHODS
A number of experiments on normal subjects were designed with the use of the vasoconstrictor bioassay technique as previously described1,2) and by a new method in which no occlusive dressings or open guards were used to cover or protect the application site. The experiments were carried out by one investigator, and vasoconstriction responses were read by an independent trained observer. The degree of vasoconstriction (blanching) is a subjective visual assessment on the part of the reader and is determined on a graded basis
where O is no blanching; 1, just detectable blanching; 2, definite but not
maximum; and 3, maximum blanching.2)
Experiment 1
This experiment demonstrated tachyphylaxis and recovery after a four-day
rest period. The corticosteroids used were 0.1% triamcinolone acetonide in
N,N-di-methylacetamide (DMAC) and 0.5% triamcinolone acetonide in DMAC. Exactly
0.01 ml of each was applied to one site on the volar aspect of each forearm of
five subjects at O, 4, 8, 24, 28, 32, 48, 52, 56, 72, and 76 hours. There
followed a rest period and a final application was made at 168 hours. No guards
or occlusive dressings were used. Subjects followed their normal routine for
clothing and bathing. The degree of vasoconstriction was noted at these times
and also at 80, 96, 172, 176, and 192 hours.
The results are tabulated as the average degree of vasoconstriction out
of ten application sites from the five subjects of each corticosteroid
concentration against time (in hours) as graphed in Fig 1.
The corticosteroid used was fluocinonide(Lidex) cream. The experiment
was conducted in an identical way except that the steroid was applied at O, 8,
24, 32, 48, 56, 72, 80, and 192 hours. Ten subjects were used and the blanching
grades are the average of 20 applications of fluocinonide cream since both
forearms are used in each subject. Readings were taken at these times and also
at 96, 198, and 216 hours. The results are seen in Fig 2.
Experiment 2
This experiment demonstrated that the vehicle used alone caused neither
vasoconstriction nor was responsible for the tachyphylaxis. The
coriticosteroids used were 0.1% triamcinolone acetonide in DMAC and 0.5%
triamcinolone acetonide in DMAC. Exactly 0.01 ml of the DMAC was applied to one
site on the volar aspect of each forearm of five subjects at O, 4, 8, 24, 28,
and 32 hours and then 0.01 ml of the corticosteroid was applied topically to these
sites without a guard at 48, 52, 56, 72, 76, 80, and 96 hours. Readings were
made at these times and also at 100 and 104 hours. The results are shown in Fig
3.
Experiment 3
This experiment demonstrated that, although recovery from tachyphylaxis
occurs after a rest period, tachyphylaxis can be induced once again. The
corticosteroids used were fiuocinonide cream and 0.1% triamcinolone acetonide
in DMAC.
The steroids were applied on alternate days at O, 7, 48, 55, and 96
hours, followed by a rest period, and the steroids were reapplied at 168, 175,
216, and 233 hours. Readings were taken at 7, 24, 31, 48, 55, 72, 79, 96, 103,
168, 175, 192, 199, 216, 223, 240, 247, 264, and 271 hours. Ten subjects were
used and each steroid was applied under an open guard. The results are shown in
Fig 4.
RESULTS
The results are tabulated graphically. The vertical coordinate
represents the average degree (grade) of vasoconstriction observed in the
application sites from all the subjects for each particular corticosteroid
concentration. The horizontal coordinate represents time (in hours) and the
application times of the corticosteroids are indicated.
Experiment I demonstrates the diminution of the vasoconstriction
response to corticosteroids applied three times daily for four days
(tachyphylaxis) and the recovery of the response after a four-day rest period.
It can be seen from the second experiment that it is not the vehicle alone but
the corticosteroid that is responsible for the vasoconstriction and tachyphylaxis.
The third experiment demonstrates tachyphylaxis to repeated steroid
applications, recovery with cessation of applications, and subsequent
tachyphylaxis if steroids are applied repeatedly once again.
During these experiments, an observation arbitrarily called the
"ring effect" was observed. Thus, when a steroid has been applied to
a site repeatedly and tachyphylaxis has occurred, if the steroid is then
applied to a greater area than it had been previously, vasoconstriction would
occur around the margin of the central nonreacting skin, forming a ring. The
peripheral area not having been primed by previously applied steroid had
presumably not developed tachyphylaxis. This effect could be a source of error
in interpreting vasoconstriction bioassays if it is not recognized.
A
statistical evaluation of the results using an analysis of variance
substantiated the graphical evidence of tachyphylaxis by indicating at the 1%
Ievel of significance that the effect of treatments are different at different
times following the initial application. However, the significance level of the
interaction factors of time, treatment, and subjects showed that the time
courses of tachyphylaxis were somewhat different for different steroids and
different subjects. Thus, in experiment 1 the maximum response (at 8 hours) to
the application of 0.5% triamcinolone acetonide is significantly different at
the 5% Ievel from that of 0.1% triamcinolone acetonide. Also, 0.5%
triamcinolone acetonide fails to give a peak response that is significantly
different from O at 52 hours whereas 0.1% triamcinolone acetonide continues to
give a significant peak response at the 5% level at 52 hours. It appears that
the stronger the steroid the greater the degree of vasoconstriction produced
initially, but tachyphylaxis occurs more quickly.
COMMENT
Tachyphylaxis has been known for many years. A typical demonstration of
this was the diminished effect on blood pressure of the sympathomimetic
agent ephedrine injected intravenously repeatedly in dogs3). The mechanism
is now explained in terms of the release of norepinephrine from storage
vesicles in the adrenergic nerve endings that attaches itself to receptors
on the effector cell, causing vasoconstriction4). Repeated stimulation
by ephedrine caused norepinephrine store depletion and the response diminished
to 0.
The exact mechanism of vasoconstriction produced by topically applied
corticosteroids is not clear. Many workers have implied a relationship between
norepinephrine and corticosteroids. Fritz and Levine5) showed that
vasoconstriction by norepinephrine in the mesoappendix of adrenalectomized rats
did not occur unless adrenal cortical extract was applied topically. Solomon et
al6) demonstrated that orally given guanethidine, a norepinephrine antagonist,
prevents topically applied steroid vasoconstriction in normotensive subjects
and suggested that corticosteroids are capable of releasing norepinephrine from
cutaneous stores. Others suggest that norepinephrine is not the only factor
involved. Reis' showed that steroids have a local and primary effect on normal
human bulbar conjunctival vessels as well as potentiating norepinephrine. Frank
et al8) showed that steroids suppress the vasodilation eaused by such agents as
histamine, alcohol, and bradykinin as well as potentiating norepinephrine. Wolf
et al9) reported in the modified hamster cheek pouch and in humans that
topically applied corticosteroids potentiated catecholamine-induced
vasoconstriction, and because this effect was blocked by phentolamine but not
by propanolol, they suggested this action might be through the increased
sensitivity ofα-adrenergic
receptors.
The demonstration of tachyphylaxis to topically applied steroids might
suggest that they act indirectly by releasing endogenous norepinephrine from
nerve storage vesicles in a similar way to ephedrine in the original dog
experiments. They might also infiuence the metabolism of the neurotransmitter
or its recapture by the vesicles after release.
Alternatively, the steroid may act by attaching itself to a receptor
site causing the release of the intracellular mediators cyclic adenosine
monophosphate or guanosine monophosphate and thus cause vasoconstriction. The
latter is probably more likely (J. J. Voorhees, oral communication, 1974),
since cyclic adenosine monophosphate is generally thought to be a dilator of
smooth muscle10), and there is some evidence now that cyclic guanosine
monophosphate is a vasoconstrictor and can be stimulated byα-receptor activity11). This receptor site might
be a specific receptor for each different steroid or a general receptor for all
corticosteroids. It is well known that intradermally injected epinephrine and
norepinephrine cause vasoconstriction and pilomotion,12,13) and it may be that
the receptor site for corticosteroids and norepinephrine are the same, although
we have never seen pilomotion with topical corticosteroids. Finally, it is
possible that corticosteroids affect cyclic adenosine monophosphate or
guanosine monophosphate in the effector cell directly either by influencing its
production or metabolism.
It
is difficult to know what the correlation is between vasoconstriction in the
normal skin and the efficacy of a topically applied steroid in the diseased
state. However, patients frequently observe that they become resistant to a
topically applied steroid after constant usage. Although there has never been
any scientific evidence for this observation, it certainly could be explained
in terms of tachyphylaxis. On the other hand it is known that topically applied
corticosteroids inhibit mitosis in normal14) and diseased skin15,16), and it
will be interesting to see whether tachyphylaxis occurs with regard to mitosis
as it does with vasoconstriction.
This investigation was supported by US Army Medical Research and
Development Command contract DA 17-67-C-7159 and National Institutes of Health
research grant AM I1649.
References
l. McKenzie AW, Stoughton RB: Method for
comparing percutaneous absorption of steroids. Arch Dermatol 86:608-610, 1962.
2. Stoughton RB: Bioassay system for
formulations of topically applied glucocorticosteroids. Arch Dermatol
106:825-827, 1972.
3. Chen KK, Meek WJ: Further studies of the
effect of ephedrine on the circulation. J Pharmacol Exp Ther 28:31-57, 1926.
4. Burn JH, Rand MJ: The action of
sympathomimetic amines in animals treated with reserpine. J Physiol
144:314-336, 1958.
5. Fritz I, Levine R: Action of adrenal
cortical steroids and norepinephrine on vascular responses of stress in
adrenalectomized rats. Am J Physiol 165:456-465, 1951.
6. Solomon LM, Wentzel HE, Greenberg MS:
Studies in the mechanism of steroid vasoconstriction. J Invest Dermatol
44:129-131, 1965.
7, Reis DJ: Potentiation of the
vasoconstrictor action of topical norepinephrine on the human bulbar
conjunctival vessels after topica] application of certain adrenocortical
hormones. J Clin Endocrinol 20:446-456, 1960.
8. Frank L, Rapp Y, Biro L, et al:
Infiammation mediatcrs and the infiammatory reaction. Arch Dermatol 89:55-67,
1964.
9. Wolf JE, Hubler WR, Guzick ND: Mechanism
of steroid-induced vasoconstriction. Read before the Society for Investigative
Dermatology meeting, Chicago, 1974.
lO. Robison GA, Butcher RW, Sutherland EW:
Cyclic AMP. New York, Academic Press Inc, 1970, pp 204-210.
ll. Schultz G, Hardman JG, Schultz K, et
al:The importance of calcium ions for the regulation of guanosine 3':5'-cyclic
monophosphate levels. Proe Natl Aead Sci USA 70:3889-3893, 1973.
12. Lobitz WC, Campbell CJ: Physiologic
studies in atopic dermatitis. Arch Dermatol 67:575-589, 1953.
13. Stoughton RB, DeOreo G, Clendenning
W:Effects of intradermal injection of vasopressors in normal and diseased skin.
Arch Dermatol 82:400-407, 1960.
14. Fisher LB, Maibach HI:The effect of
corticosteroids on human epidermal mitotic activity. Arch Dermatol 103:39-44,
1971.
15. Fry L, McMinn RMH: The action of
chemotherapeutic agents on psoriatic epidermis. Br J Dermatol 80:373-383, 1968.
16. Baxter D. Stoughton RB: Mitotic index
of psoriatic lesions treated with anthralin, glucocorticosteroid and occlusion
only. J 1levest Dermatol 54:410-412, 1970.
付記
米国では（英語論文であるので、世界的にと読み替えてもいい）1970年代中頃には既に、ステロイドの連日外用でその効果の減弱する事が広く認められています。このことを示す論文がこの二編です。
1) du Vivier A, Stoughton RB: Tachyphylaxis to the action of topically applied corticosteroids. Arch Dermatol 111: 581-583, 1975
2) Singh G, Singh PK: Tachyphylaxis to topical steroid measured by histamine-induced wheal suppression. Intern J Dermatol 25: 324-326, 1986
1) 外用ステロイドの作用に対する効果減弱反応
2) ヒスタミンで誘発される膨疹が抑制される事によって分かる外用ステロイドに対する効果減弱反応
１）では、日に2-3回外用すると3-4日で血管収縮効果がほぼ消失し、3-4日の無外用で血管収縮効果が元に戻る事を示し、
２）では、毎日ステロイドを外用していると、人工的に作る蕁麻疹を抑える作用が8日目に最高に達するがその後減弱し、14日目には蕁麻疹発生を全く抑制しなくなるということを示している。
このように、外用ステロイドの連続投与では直ぐに効果が無くなる事が実験的に証明されている。
日本のアトピー性皮膚炎患者は医師に、ステロイドの外用効果が無くなる事を訴えるが医師にはなかなか認めてもらえないでいる。前述二論文のなかの「はじめに」に当たる部分に共通して次の事が述べられている。「初めは劇的に効くが、持続的に使用しているとその効果は減弱するというしばしば聞かれる患者の訴え」や「臨床現場では、患者は時々、ステロイドの効果が反復持続外用によって減弱すると訴える」と。このことは、持続外用によってステロイドには効果減弱反応が起こるということが1970年代中頃の米国では広く認められていることを意味している。これの反映がPhysician's Desk Reference の中にある「小児には3週間以上の長期使用の効果と安全性は確認されていない」という言葉となっているのであろう。
しかるに日本皮膚科学界の中枢部の人間にはこのことがなかなか認識できない。何らかの理由でこのことに目をつぶっているのであろう。多くの患者が「ステロイドが効かない」あるいは「皮膚が薄くなったり痒くなったりするのは外用治療の副作用と思う」ために民間療法に走り、多くの無駄金を使わされているというのに。そして、患者が民間療法に走るのは脱ステロイドという「非科学的な」治療方法を宣伝する一部の「悪い」医師がいるためであると宣伝している。患者の訴えをよく聞かなければならないという彼らの言葉をどのように考えればいいのであろうか。アトピー性皮膚炎に対するステロイド外用に対する問題提起が激烈であったことで事の本質を見失うようでは科学者としては問題である。彼らの猛省を促す必要がある。
ステロイド依存症と効果減弱反応とはよく似ているが違うものであろう。前者は、ステロイド無しには皮膚全体の普通の代謝ができない状態であり、後者は皮膚の特定の反応が減弱しているだけであると考えられる。従って、おそらく境界ははっきりしないであろうが、後者は前者の入り口に存在する状態であろう。