The article is an effort to highlight the prominence and relevance of
chirality in pharmacotherapy. As evident the main partners in
pharmacotherapy are the patient (biological system) and the medicines.
About 70 per cent of new small-molecule drugs that the Food & Drug
Administration approved in 2007 contained at least one chiral molecule
as its central active component.
Chirality or handedness is the
phenomenon described when an object cannot be superimposed on its
mirror-image (Fig.1). The medicines are designed to interact with the
biological system, which is highly chiral, and bring out the desired
therapeutic response. Human system is a classical chiral environment
being built up of chiral discriminators viz. proteins, and
carbohydrates. So we find that in most cases both the partners in
pharmacotherapy are handed. As a consequence one can expect the
interactions to be enantioselective and will have significant clinical
implications.
For a better understanding of the situation one
need to look into the various biological events the drug molecule
travels through before eliciting a pharmacological effect which could be
desired response or a toxic/side effect. The events of biological
actions can be classified into three phases namely pharmaceutical,
pharmacokinetic (PK) and pharmcodynamic (PD). In all the three phases
one can expect enantioselectivity if the drug molecule under question is
a racemate. There are studies that go to show that the release of
enantiomers of chiral drugs from pharmaceutical formulations containing
chiral excipients can be enantioselective.
Most pharmaceutical
excipients employed in formulations are chiral. It is not surprising to
observe enantioselectivity in the pharmacokinetic process. All the PK
processes viz. absorption (active), distribution, metabolism and
elimination are mediated by enzymes and most enzymes are chiral. Hence
PK processes may be handed. PD phase where the actual interaction of the
pharmcophoric group of the drug with the receptor happens is
three-dimensional in nature. The Easson-stedman model offers simple
explanation for these kinds of interactions.
Since so many drugs
in common use are chiral, the question that would pop-up is whether
patients would obtain more benefit from either single enantiomer rather
than the racemate currently in use. Also, if an enantiopure drug is
currently used, is it in fact the better one? In responding these
questions, the overriding criterion is not whether one enantiomer is
more active or more toxic than the other, as is often the case.
More
important is the therapeutic index of each enantiomer i.e., the margin
between efficacy and safety. Examination of the cases of racemic
therapeutics where enantiomers have been evaluated separately for their
activities reveals the following categories from a clinical perspective
viz. Racemate currently used: clinically acceptable; Racemate currently
used: enantiopure drug preferable; Enantiopure drug currently used:
clinical advantage; Enantiomer developed to replace racemates: chiral
switches.
Racemate currently used: clinically acceptable
Racemic
warfarin is a well established in drug therapy. It is documented that
S-warfarin is about 3-5 times more potent than the mirror-image twin
(R-warfarin). A chiral switch to the S-enantiomer would merely alter
the dosage requirement without any significant gain in the therapeutic
index. Nevertheless the gain from using the chirally pure drug would be
outweighed by the cost involved in producing them. Like racemic
warfarin, racemic propranolol is well established in drug therapy and
there is no evidence to suspect that the isomeric ballast provided by
d-propranolol, which has less b-blocking activity than l-propranolol, is
a weakness in the treatment of angina and hypertension.
Racemate currently used: enantiopure drug preferable
At
times there is a genuine clinical reason for developing a single
enantiomer of a previously marketed racemic therapeutic. The anesthetic
Ketamine is available as a racemic mixture. S-ketamine has the
desired activity (referred to as the eutomer) where as the other
enantiomers (referred to as distomer) harbors the psychomimetic effects,
which limits the clinical use of the racemate. It would seem preferable
to use the more potent and less toxic S-enantiomer rather than the
racemate.
Racemic sotalol is used as an antiarrhythmic agent but
the ß-blocking activity of (R)- sotalol is a problem in patients with
failing hearts. The (S)-sotalol has significant class III
anti-arrhythmic activity and is not a b-blocker. Hence the use of
(S)-enantiomer instead of the (R)-enantiomer provides an advantage from
clinical viewpoint.
Enantiopure drug currently used: clinical advantage
There
are compelling evidences supporting the clinical use of chirally pure
forms in pharmacotherapy. Ethambutol, the tuberculostatic agent, is an
old drug that is marketed in the enantiopure form. Ethambutol introduced
for clinical use is (+)-ethambutol with an (S, S)-stereochemical
configuration. Compared to the (+)-isomer, the (-)-isomer had about
1/500th of the required antibacterial activity while the meso-isomer was
only 1/12th as active. In contrast, all the three isomers were almost
equipotent in terms of their potential to produce the major side effect
of the drug, ocular neuropathy. This side effect was related to the dose
and duration of the treatment with the drug. The risk/benefit ratio of
the treatment with ethambutol was greatly enhanced by marketing the
(+)-enantiomer.
Other older drugs which have been used in
chirally pure form include L-dopa and D-penicillamine. Although
enantioselectivity in their toxicity was recognized, both were
originally used a racemates until it was possible to produce pure
enantiomers in a commercial scale. L-dopa is absorbed selectively by
active processes and it is the D-dopa which is associated with
granulocytopenia. Similarly D-penicillamine is far less prone to serious
nephrotoxicity than L-penicillamine and hence D-penicillamine is
preferred over L-enantiomer in the treatment of Wilson’s disease. These
drugs are marketed as unichiral solely because their toxicities reside
almost exclusively in one of the chiral twins.
Further familiar
but less well appreciated examples of enantiopure chiral drugs in
clinical use are (S)-timolol, (S)-naproxen, levamisole, (+)-methorphan
which is an over the counter antitussive while (-)-methorphan is a
controlled narcotic and (+)-propoxyphene which is a potent analgesic
while (-)-propoxyphene is an active antitussive.
Enantiomer developed to replace racemates: chiral switches
A
racemic or chiral switch may be defined as the development of a single
enantiomer from a previously marketed racemate. Chiral purification is
primarily intended to introduce single-enantiomer versions of the
existing racemates which offer greater therapeutic value. It is observed
that the innovator drug companies sometimes employ this approach as a
defence strategy to rejuvenate the commercial life of a racemate whose
patent protection is nearing expiry.
A classical example that
fits into the first category is the chiral switch of ofloxacin to
levofloxacin. Ofloxacin is fluoroquinolone, on the market since 1987 as a
racemic mixture. The antibacterial activity mainly reside in the
(-)-enantiomer (levofloxacin). From the microbial standpoint
levofloxacin is 128 times more effective than the (+)-enantiomer and
twice as effective as the racemate according to the gram positive and
gram negative bacterial stocks assayed. Levofloxacin and ofloxacin has
similar pharmacokinetic profile. Of particular clinical interest is the
extension of the spectrum with respect to Streptococcus pnuemoniae
(pneumococcus). In fact, the main guidelines on the treatment of
community acquired pneumonia mention levofloxacin (and not ofloxacin)
among the fluoroquinolones with activity against pneumococcus. The
levofloxacin, S-(-)-isomer of ofloxacin, has an important clinical
advantage over racemic ofloxacin.
The three single-enantiomer
versions of widely used racemic drugs viz. esomperazole (from
Omeprazole), levalbuterol (from Albuterol) and Escitalopram (from
Citalopram) are examples of chiral switches that falls into the second
category of commercial motives.
The potential markets for each
of these are large because they are used for common conditions: reflux
oesophagitis, asthma and depression. In the all the three cases the
claims of increased efficacy were based on comparisons of non-equivalent
doses and any advantage seemed small and clinically unimportant. The
prices of esomperazole and levalbuterol were higher than their racemic
alternatives. The enantiopure drugs marketed for these common diseases
do not have valuable clinical advantage over the racemic products they
were being promoted to replace.
There are chiral switches that
have been failures. For example the clinical development of
(R)-fluoxetine for depression was stopped because of statistically
significant prolongation of the QT interval with high doses. Dilevalol
(the chiral switch of labetalol) was thought to have advantage over
labetalol, but was withdrawn from the Japanese market because of
hepatotoxicity. The experience of chiral switching so far has been not
very satisfying. Although chiral switching has not been a success for
scientific medicine, it has been an achievement for scientific
marketing.
There are number of unichiral introductions in the
Indian market including(S)-amlodipine, (S)-atenolol, (S)-metoprolol,
(S)-pantoprazole, eszopicolone, (R)-ondasterone, levocetrizine, and
dexibuprofen.
Conclusion
The consequences of
enantioselective pharmacokinetics, pharmcodynamics and toxicology of
chiral drugs are not only a curious scientific phenomenon but have an
array of implications in pharmacotherapy. This reinforces the need for
pharmacists to educate themselves regarding issues pertaining to drug
chirality and pharmacological consequences.
The burgeoning
knowledge about the structure of various sites of action of drugs,
exponential explosion of chiral technology and an increased awareness of
possible disadvantages of using racemic therapeutics would be expected
to result in increased marketing of enantiopure drugs in future. The
potential benefit of enantiopure medicines include less complex, more
selective pharmcodynamic profile, less complex pharmacokinetic profile,
improved therapeutic index and reduced potential for complex drug
interactions.
In this context, for effective clinical practice
pharmacists as the drug experts must be aware of the relevance of
chirality and be able to translate scientific data as well as clinical
knowledge clearly to the patient and other members of the allied health
care team. The pharmacist’s ability to provide pharmaceutical care will
depend on their ability to educate themselves on the issues of
chirality, and their willingness to assume greater responsibility in
communicating with patients regarding these issues.
It is the
responsibility of the pharmacists to provide update information on
chiral drugs especially racemic forms to healthcare professionals to
enable them to find an optimal treatment and achieve a right therapeutic
control. Physicians need to reassess the rationality of existing
racemates and also determine the clinical value of recent enantiopure
introductions. For chiral drugs a mirror-image perspective in
pharmacotherapy is vital and valuable to ensure that the left hand knows
what the right hand is doing.
The author is Professor, Department of Pharmacy, Annamalai University Annamalainagar, Tamil Nadu