Download Rectal drug delivery: A promising route for enhancing drug absorption

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Asian J. Res. Pharm. Sci. 2012; Vol. 2: Issue 4, Pg 143-149
ISSN- 2231–5640 (Print)
www.asianpharmaonline.org
ISSN- 2231–5659 (Online) 0974-3618
REVIEW ARTICLE
Rectal drug delivery: A promising route for enhancing drug absorption
Lakshmi Prasanna J.*, Deepthi B., Rama Rao N.
Department of Pharmaceutics, Chalapathi Institute of Pharmaceutical Sciences, Lam, Guntur- 522034
*Corresponding Author E-mail: [email protected]
ABSTRACT:
Rectal drug delivery is an efficient alternate to oral and parenteral route of administration in partial avoidance of first
pass metabolism and protein peptide drug delivery. This route allows both local and systemic therapy of drugs.
Controlled absorption enhancement of drugs can be achieved by the rectal route because of the constant conditions in
the rectal environment. In the present review various absorption enhancers with their mechanism of action in
improving drug absorption through rectal epithelium and the potential of rectal route in delivering protein and
peptides, analgesics and antiepileptics are discussed. This review also presents affects of various absorption promoting
adjuvant on the rectal absorption of drugs.
KEYWORDS: Rectal absorption, enamine derivatives, salicylates, fatty acids, cyclodextrins, protease inhibitors
INTRODUCTION:
ANATOMY AND PHYSIOLOGY OF RECTUM:
The rectal route though rarely the first choice of drug
administration serves as an alternative to oral and invasive
administration. Rectal drug delivery is so pivotal when the
oral medication is not possible, Intra venous access is not
possible and the patients have difficulty in swallowing,
nausea and vomiting and for infants or children. Rectal
route offers potential advantages for drug delivery. They
include: rapid absorption of many low molecular weight
drugs, partial avoidance of first pass metabolism, potential
for absorption into the lymphatic system, retention of large
volumes, possibility of rate controlled drug delivery and
absorption enhancement.1,2 However this route also has
some disadvantages: many drugs are poorly or erratically
absorbed across the rectal mucosa, a limited absorptin
surface area, dissolution problems due to the small fluid
content of the rectum, drug metabolism in micro organisms
and rectal mucosa. To overcome these, various absorption
enhancing adjuvants, surfactants, mixed micelle and
cyclodextrins were studied. In this review various
absorption enhancers, their effects along with the role of
rectal route in delivering various drugs has been discussed. 3
The rectum comprises of the last portion of the large
intestine and extends 12 -18cm distally. The rectum has 2 or
3 curves within its lumen created by submucosal folds
called the valves of housten.4 It can be considered as hollow
organ with a relatively flat wall surface without vili. The
rectal wall is formed by an epithelium which is one cell
layer thick and composed of cylindrical cells and goblet
cells which secret mucus. The surface area available for
drug absorption in the rectum is approximately 200400cm2.1,2 Volume of fluid in the rectum is about 1-3ml and
is viscous. The rectal mileiu is constant as its pH is about
7.5-8; the temperature is usually 37°C. Three separate veins
comprise the venous drainage of rectum. The superior rectal
vein drains the upper rectum and then empties into the
rectal vein which flows into the liver. The middle and
inferior rectal veins drain the remainder of the rectum and
return to the inferior vena cava. Vasculature of the rectum is
shown in Figure 1. It is normally empty and filling of
rectum provokes a defecation reflex which is under
voluntary control. 4, 5
AVOIDANCE OF FIRST PASS ELIMINATION:
Received on 01.10.2012
Accepted on 04.11.2012
© Asian Pharma Press All Right Reserved
Asian J. Res. Pharm. Sci. 2(4): Oct.-Dec. 2012; Page 143-149
Rectal administration of drugs partially avoids hepatic first
pass metabolism. The superior rectal vein which peruses the
upper part of the rectum drains into the portal vein and
subsequently into the liver where as the middle and inferior
rectal veins drains the lower part of the rectum and enter
into the inferior vena cava and bypass the liver before
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entering the general circulation. This indicates the drug
administered in the lower part of the rectum can bypass the
liver resulting in the avoidance of hepatic first pass
metabolism and increases systemic circulation. This was
investigated and proved with lidocaine, a hepatic high
clearance drug. When lidocaine as an osmotically controlled
release dosage form, administered low into the rectum
resulted in low concentration of first pass metabolite of
lidocaine and high concentration of lidocaine. This is an
indicative for decreased first pass elimination. The same
result was found with proponalol and also increased rectal
bioavailability of morphine in man while results with
oxeprenolol were disappointing with only half of the
bioavailability of the oral preparation. This may be due to
the rectal irritation caused by the drug leading to increased
peristalsis and defecation. It can be concluded that hepatic
first pass elimination can be partially avoided by the drug
administration in the lower part of the rectum. 6
Fig 1: Vasculature of rectum, 1: middle rectal vein; 2: tunica
muscularis: stratum longitudinale; 3: m. levator ani; 4: inferior
rectal vein; 5: m. sphincter ani externus; 6: superior rectal vein; 7
and 8: plexus venosus rectalis (submucosus); 9: skin; 10: v.
marginalis
ABSORPTION OF DRUGS IN RECTUM
Absorption of drugs from rectal epithelium involves two
transport routes: the transcellular route and paracellular
route. 7 An uptake mechanism in transcellular route depends
on lipophilicity where paracellular route is drug diffusion
through a space between epitelial cells. Rectal absorption of
drugs is dependent on several drug characteristics such as
partition co efficient and molecular size. Small partition
coefficient, large molecular size, charge and high capability
of hydrogen bond formation are the typical factors
identified for poor absorption of drug. Another significant
hindrance is the presence of faeces which also can alter the
drug absorption. Solutions, suspensions and suppositories
are the common dosage forms for rectal administration of
drugs. Rectal contents are generally alkaline and alkaline
solutions are quickly absorbed than acid solutions. 8
Aqueous and alcoholic solutions are absorbed quickly
where as suspensions and suppositories exhibit slow and
continuous absorption. Primary methods utilized in
improving rectal absorption of the drugs include
•
•
•
Formulation modification to improve dissolution step
of poorly aqueous soluble drugs.
Modification of the barrier functions of the rectal
mucosal membrane.
Chemical modification of drug to increase partition co
efficient. 9
ABSORPTION ENHANCERS:
The need to find non invasive routes of protein and peptide
administration has focused attention on the other routes of
administration. Protein peptide drug delivery by rectal
offers the following advantages: low levels of protease
activity particularly of pancreatic origin and avoidance of
first pas metabolism. However bioavailability of therapeutic
proteins and peptides following rectal administration in the
absence of absorption enhancers is low. 10 Various
absorption promoting adjuvants with their mechanism of
action are discussed here.
Enamine derivatives as absorption enhancers
There have been many investigations of the action of amino
acid enamines (phenylalanine and phenylglycine) of betadiketones (ethylacetoacetate) for enhancing rectal
absorption. Because of the rapid absorption of enamine and
the chelating capability of ethylacetoacetate and enamine
derivatives, research to investigate the feasibility of
enamine derivatives of amino acids as absorptionpromoting adjuvant has started. Formation of amino acid
with ethylacetoacetate in aqueous solution increases with an
increase in the pH of the solution. 9 The enhancing action of
enamine derivatives on rat rectal absorption of CMZ (a
hydrophilic antibiotic) is dependent on enamine formation
capability. The action of the enamines appeared only for
short periods due to rapid absorption of the enamines and
degradation at the site of action (hydrolysis in aqueous
phase). 11
An increase in serum insulin after rectal administration of
an insulin suppository containing an enamine occurred
rapidly, but the disappearance of serum insulin also
occurred rapidly in de-pancreatized dogs. When an enamine
suppository without insulin was administered at 20 min
after dosing with an insulin suppository containing
enamine, an increase in serum insulin concentration was
observed after the second administration of the enamine
suppository. This result indicates that the time period during
which enamines enhance rectal insulin absorption is very
short.12,13 A detailed study of the mechanism for the
adjuvant action of enamines has not yet been reported.
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concentrations which are reached at therapeutic doses. 21,22
Salicylate and 5MSA are found to inhibit metabolism from
lactate to pyruvate in TCA cycles. Thus, co-administration
of salicylate or 5MSA with insulin in a suppository may
induce a synergistic therapeutic effect as well as an
A primary concern of enamine derivatives for use in absorption promoting effect. Salicylate and 5MSA were
formulation development is the stability of the enamines proved as safe adjuvants by cytological studies. 9
themselves. In many cases, they undergo rapid hydrolysis at
neutral or lower pH values and in suppository bases Fatty acids
containing moisture. Acute toxicity data in rats did not There are many reports about the enhancing action of fatty
show any toxicity up to 1500 mg/kg and furthermore, rapid acids on rectal and small intestinal absorption. Medium
hydrolysis of enamines may reduce the probability of toxic chain length fatty acids showed the most effective action as
effects. 9,11
absorption-promoting adjuvants for ampicillin and
hydrophilic antibiotics for rectal delivery. It has been
reported that the enhancing action of fatty acids is
Salicylates and its derivatives
There are many reports of the utility of salicylate and its dependent on the partition coefficient. The optimal partition
derivatives as adjuvants in promoting rectal absorption of coefficient was calculated at log P = 4.2. This apparent
hydrophilic antibiotics and polypeptides. The enhancing correlation with partition coefficient indicates that the
action of salicylate depends on its concentration at the site uptake of fatty acids into rectal tissue must be a key factor
of action. It promotes absorption of both low and high in their potency as absorption-promoting adjuvants. 23 With
molecular weight compounds.14 Analogues of salicylate respect to long chain fatty acids such as oleic acid, dosing
such as 5-methoxysalicylate (5MSA) have also been of oleic acid itself does not cause significant enhancements
demonstrated as absorption enhancer. Permeability of for the rectal absorption of hydrophilic antibiotics, but when
trypan blue in the form of micro enema has been enhanced dosed in a mixed micelle formulation prepared with sodium
in the rectal lumen by salicylate at a concentration of 2%. taurocholate, significant absorption promoting action
Reversibility of the effect was clearly shown by exposing appeared.24 Murakami et al. have reported that the adjuvant
the rectal epithelium to salicylate, rinsing out the salicylate action of fatty acids was suppressed by pretreatment with
after 15 min. and then demonstrating that the epithelium N-ethylmaleimide, a sulfhydryl modifier; i.e. one of the
action sites of fatty acids must be the protein fraction of the
was impermeable to trypan blue. 15
plasma membrane.25
Rectal bioavailability of antibiotic depends both on the
concentration of the adjuvant and on the dosage form. A Strong chelating agents
lipophilic suppository base seems to provide a satisfactory Strong chelating agents such as EDTA and EGTA have
vehicle for the delivery of several antibiotic drugs resulting been employed for the study of tight junctions between
in good rectal bioavailability. The use of a lipophilic intestinal epithelial cells. Treatment of the intestinal
suppository base can easily maintain a high concentration epithelium by strong chelating agents resulted in loosened
of the adjuvant in the rectal compartment segment in tight junctions, which induce an increase in diffusion of
comparison to an aqueous micro enema, because salicylate solutes through tight junctions. 26 Further, strong chelating
easily dissolves when dosed as the sodium salt. 5MSA has agents inhibited the aggregation of isolated intestinal
been reported as stronger absorption enhancer when epithelial cells by removing or masking Ca 2+ on the surface
compared to salicylate. Because melting of a triglyceride of the isolated intestinal epithelial cells. EDTA increases
base occurred rapidly, the release and dissolution of both the transport of both antipyrine (relatively small molecular
the adjuvant and the antibiotics also occurred rapidly in the weight) and phenol red (relatively larger molecular weight).
rectal cavity.16,17 Both salicylate and 5MSA also increase The transport enhancing action of EDTA was inhibited by
the rectal absorption of insulin, heparin, gastrin and ouabain which is a Na+, K+-ATPase inhibitor.20
pentagastrin administered in micro enemas to rats. 18,19 The
action of salicylate in inhibiting cell aggregation may relate Sulf hydryl depleter
to the adjuvant action of salicylate in enhancing the Nishihata et al. found that there was a relationship between
paracellular
transport
route
at
high
salicylate non-protein thiol content and membrane permeability in
concentrations. Salicylate may inhibit cell aggregation by isolated rat intestinal cells. When the isolated cells were
two possible mechanisms; i.e. salicylate may modify the treated with diethyl maleate (DEM) at high concentrations
cell surface function responsible for binding aresenazo III of 5 mM for a short period of time (before apparent cell
and/or inactivation of calmodulin by decreasing the Ca2+ death). A significant loss of both non-protein and protein
concentration in the cytosol. 20
thiols occurred and cell membrane permeability against
water soluble antibiotics decreased. Protein thiol loss
Salicylate is transported primarily through epithelial cells at induced by high concentrations of DEM was inhibited by
low concentrations, but salicylate is transported via the the co-presence of calmodulin inhibitors in the media of the
intercellular route through tight junctions at high isolated cells. However, calmodulin inhibitors did not
Because enamines can enhance the rectal absorption of
relatively large molecular weight compounds such as
insulin and even a stronger action of enamine was observed
for relatively small drugs.
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provide for the recovery of the loss of non-protein thiol by
DEM. Further, when protein thiol loss by a high
concentration of DEM disappeared in the co-presence of a
calmodulin inhibitor but non-protein thiol loss continued,
the cell membrane permeability against water soluble
antibiotics increased again. Thus, non-protein thiol loss
induced an increase in cell membrane permeability with
respect to water soluble compounds which have relatively
small molecular weights.27,28
Enhancing mechanism of absorption enancers
The mechanisms whereby absorption enhancers improve
the absorption of proteins and peptides involve increase in
membrane fluidity, expansion of the dimension of the
intercellular space, Solubilization of the mucosal
membrane, increase in water flux, and reduction of the
viscosity of the mucus layer adhering to all mucosal
surfaces.29
Efficacy and safety of absorption enhancers
In the study conducted to compare the absorption
promoting ability of a poorly absorbed compound (phenol
red) and local intestinal damage by different enhancers
(sodium glycocholate (Na-GC), sodium taurocholate (NaTC), sodium deoxycholate (Na-DC), EDTA, sodium
salicylate, sodium caprate (Na-CAP), diethyl maleate, nlauryl-β-D-maltopyranoside (LM), linoleic acid with
HCO60 mixed micelle), Na-DC, EDTA and LM proved to
be the most effective enhancers. 30
Thus a number of absorption enhancers have been utilized
for improving rectal absorption of larger polypeptides and
proteins.
Protease inhibitors
Low bioavailability of proteins and peptides by oral route is
due to poor membrane permeation characteristics and
hydrolysis by digestive enzymes. Therefore, the use of
protease inhibitors, which could reduce the degradation of
various peptides and proteins due to the inhibition of
protease activities at absorption sites, is one of the
promising approaches to overcome the delivery problems of
these peptides and proteins. Protease inhibitors include
aprotinin, trypsin inhibitors, bacitracin. puromycin. bestatin
and bile salts such as Na-GC. 31 Morishita et al. examined
the effect of aprotinin on the hypoglycemic effects of
insulin after administration to the duodenum, the jejunum,
the ileum and the colon using an in situ loop method and
suggested that the effect of aprotinin on intestinal
absorption of insulin was site-dependent and the ileum is
thought to be suitable for insulin delivery. 32
were stabilized by these inhibitors were not fully
understood. 31
Chemical modification of protein and peptide drugs
The absorption enhancers and protease inhibitors can
enhance the absorption of normally non-absorbed
molecules from the gastrointestinal tract. However,
limitations such as local irritation of the mucosa and nonselective absorption of other antigenic compounds are
considered drawbacks in the use of absorption enhancers. A
potentially useful approach to solve these delivery problems
may be chemical modification of peptides and proteins to
produce prodrugs and analogues. The intestinal absorption
of insulin was known to be very poor due to its extensive
degradation by various peptidase and digestive enzymes
and poor membrane permeability characteristics. Acyl
derivatives of insulin were synthesized to improve the
gastrointestinal absorption of insulin. The acyl derivatives
of insulin were synthesized by protecting the amino group
of glycine-Al, because this group is essential for insulin
activity. Chemical modification with fatty acids improved
lipophilicity of insulin with increasing carbon numbers of
fatty acids attached to the native insulin with increased
intestinal absorption and permeation of insulin.
Human calcitonin (hCT) which consists of 32 amino acid
residues is one of the calcium regulating hormones.
Calcitonin is clinically used for the treatment of increasing
bone resorption in metabolic bone disorders such as postmenopausal osteoporosis in older women. Calcitonin was
chemically modified with acetic and caproic acids to
improve lipophilicity. The lipophilic index value increased
with increasing carbon number of fatty acids attached to
hCT, indicating that the acylation of hCT enhanced its
lipophilicity. The pharmacological activity of hCT was
reduced with increasing the carbon numbers of fatty acids
introduced to hCT. The half-lives were significantly
prolonged by chemical modification with fatty acids in both
small and large intestines, indicating that the acyl
derivatives were more stable than the native hCT. The
extent of the promoting effect was a little higher for a native
hCT rather than for acyl-hCT derivatives. These results
suggested that it may be possible to achieve the further
absorption enhancement of hCT by using a combination of
acylation and absorption enhancers.
The acylated peptides with an appropriate lipophilicity may
improve stability against various enzymes and may be
passively transported by their increased lipophilicity.
Furthermore, the acylation also increased the absorption of
peptides such as thyrotropin releasing hormone (TRH) and
Phe-Gly which are transported by a carrier-mediated
From various studies it may be considered that the action of process. These findings suggested that lipophilicity may be
these protease inhibitors to the mucosal membrane was one of the most important factors for increasing the
reversible and non-toxic. Consequently, the use of protease membrane permeation of drugs. 31
inhibitors is one of the most useful approaches to improve
the stability and absorption of peptides and proteins,
although the mechanisms whereby peptides and proteins
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Cyclodextrins in rectal drug delivery
Cyclodextrins (CDs), cyclo oligo saccharides consisting of
several glucopyranose units are host molecules which form
inclusion complex. The three CDs α-CD, β-CD and γ-CD
were reported to be useful for rectal drug administration
with respect to stabilization, improvement in release and
bioavailability and alleviation of local irritation. Parent CDs
have been chemically modified to extend physico chemical
properties and inclusion capacity of parent CDs. The
hydroxyl groups of parent CDs were used as a starting point
for chemical modifications of the molecule. Generally, the
CD derivatives can be divided into three groups;
hydrophilic, hydrophobic and ionizable derivatives. The
hydrophilic derivatives included have methylated CDs such
as 2,6-dimethyl-β-CD (DM-β-CD) and 2,3,6,-trimethyl-βCD (TM-β-CD), hydroxyalkylated CDs such as 2hydroxypropyl-β-CD(HP-β-CD) and branched CDs such as
maltosyl-β-CD (G2-β-CD), which can augment the aqueous
solubility and dissolution rate of poorly water-soluble
drugs. The hydrophobic CDs include ethylated CDs such as
2,6-diethyl-β-CD (DE-β-CD), which can retard the
dissolution rate of water-soluble drugs. In addition, the
ionizable CDs include O-carboxymethyl-β-CD (CM-β-CD),
O-carboxymethyl-O-ethyl-β-CD
(CME-β-CD),
β-CD
sulfate and sulfobutylether β-CD (SBE-β-CD), which can
realize the improvement in inclusion capacity, the
modification of dissolution rate and the alleviation of local
irritation of drugs, etc, while the hydrophobic CDs may
modulate the release of drugs from the vehicles.
morphine to glucorides of morphine. The inhibitory effects
of α-CD on the glucoronate conjugation of morphine could
be ascribed to the inhibition of the upward movement of
morphine from areas which are impacted by first pass
metabolism. 34
CDs were also reported in enhancing the release of drugs
from suppositories. It has been proposed that the enhancing
effects of parent CDs on the release of lipophilic drugs from
the oleigenous suppository bases could be attributed due to
the formation of more hydrophilic complexes of these
drugs, because these complexes are of low affinity with the
base and rapidly dissolve into the rectal fluids. In
comparison with parent CDs, DM-β-CD or HP-β-CD
enhance the rectal absorption of lipophilic drugs like EBA
to a greater extent. Complexes of β-CD, DM-β-CD, TM-βCD and ethyl 4-biphenylacetate (EBA) also inhibited the
bioconversion of EBA in rat rectal lumen and HP-β-CD has
higher potential to improve the rectal absorption of EBA
when compared to β-CD and DM-β-CD complexes. 35
There are some reports on the use of CDs as co enhancer.
Rectal administration of cefmatazole sodium suppository
with inclusion complex of decanoic acid, an absorption
enhancer with α-CD complex as an additive increased the
plasma concentration significantly than those without
additive. 36 However negative effects of CD combination
were also reported. The mixture of β-CD and
hydroxypropylmethyl cellulose markedly reduced the
bioavailability of acetaminophen from both aqueous
solution and hydrogels. The lower partition coefficient and
the higher hydrophilic property of the β-CD complex and
the higher viscosity of HPMC hydrogel matrix might be
responsible for the decrease in the rectal absorption. 37
Recently reduction of drug irritancy in rectal delivery by
CDs has been reported. HP-β-CD significantly reduced the
irritation of the rectal mucosa caused by EBA after the
single and multiple administrations of oleaginous
suppositories to rats.35,38
Enhanced rectal absorption of lipophilic drugs by CDs is
based on the improvement of release from vehicles and the
dissolution rates in rectal fluids, Whereas in absorbable
drugs such as antibiotics, proteins and peptides is based on
the direct action of CDs on the rectal epithelial cells. Many
reports have indicated findings that the effects of CDs on
the rectal delivery of drugs markedly depends on vehicle
type (hydrophilic or oleaginous), physicochemical
properties of the complexes and an existence of tertiary
excipients such as viscous polymer, etc. prolonged drug Table 1: The use of cyclodextrins in rectal delivery
CDs
Improvement
Drugs
release effects of CDs is caused by the sustained release
α-CD
Stability
Morphine hydrochloride
from the vehicles, slower dissolution rates in the rectal fluid
Release and/or
Cefmetazole
or the retardation in the rectal absorption of drugs by an in
permeation
Morphine hydrochloride
absorbable complex formation. Various parent CD and
β-CD
Stability
Carmofur
Ethyl 4-biphenylyly acetate
derivatives of CDs used in rectal drug delivery are given in
Release and/or
Naproxen
Table 1. 3
permeation
CDs may improve the chemical stability of drugs in the
rectal suppository base. TM-β-CD and DM-β-CD complex
with carmofur (a prodrug of 5-flourouracil and apts to
hydrolyze to 5-flourouracil) were reported to have greater
stability than carmofur in oleagenous suppository bases.
The stability of β-CD and DM-β-CD is due to
insolubilization of these drugs in the oleagenous
suppository base and which may lead to a difficult
interaction of drugs with the base. 33 CDs may inhibit the
bioconversion of drugs in the rectum. A combination of αCD and xanthan gum has inhibited the bioconversion of
147
γ-CD
DM- C
Release and/or
permeation
Release and/or
permeation
Local irritation
TM- β-CD
HP-β-CD
β-CD polymer
Release and/or
permeation
Release and/or
permeation
Selective transfer
into lymphatics
Phenobarbitol
Piroxicam
Diazepam
Flubiprofen
Diazepam
Flubiprofen
Insulin
4-biphenylacetic acid
Ethyl 4-biphenylyly acetate
Diazepam
Flubiprofen
Diazepam
4-biphenylacetic acid
Carmofur
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Rectal administration of the anti epileptic drugs
Therapeutic concentration of the drug must be maintained
for optimal seizure control in both acute and chronic
treatment of epilepsy. When chronic administration of
medication is required but due to lack of oral access and
incompatibility of IV formulation of medication alternative
routes of drug dosing is required. Importance of rectal route
in anti epileptic drug administration is partial avoidance of
first pass metabolism. Diazepam by rectal route as solution
and gel preparation has been used for several decades for
treating repetitive or prolonged seizures in children.
Diazepam solution administered rectally result in rapid and
complete absorption with peak plasma concentration
attained within 5-15 min. the rectal formulation of
carbamazepin as a dilute suspension, a viscous gel solution
containing equal amount of drug and HPMC and
suppositories have been found to be bioequivalent to
administration as oral tablets and oral suspension. 39-43
Evidences show that rectal administration is feasible for
lamotrigine, levetiracetam, phenobarbital, topiramate and
valproate.44
Analgesics by rectal route
Analgesics are probably the most frequently used rectal
medications in palliative care. Various opioids have been
used rectally to treat cancer pain. Morphine is probably the
most useful of these opioids. Morphine when given by oral
route undergoes extensive first pass metabolism and has a
bioavailability of 30-40%. Administration by the rectal
route should theoretically avoid most of the first pass
metabolism. In a study conducted by Maloney et al, in
terminally ill patients who received various doses of
controlled release morphine tablets by rectal route, most of
the patients experienced equivalent analgesic action by the
rectal route as with oral tablets with no side effects and in
few patients the analgesia was maintained without any side
effects though the dose of the drug was reduced because of
drowsiness.45
Babul et al compounded two different preparations of
controlled release morphine suppositories a high viscosity
and a low viscosity preparation. Both preparations were
observed o a greater extent (larger AUC) than oral
controlled release tablets but the peak concentrations was
slightly lower and the time to peak was significantly
prolonged as compared with oral tablets. 46 From various
studies it was concluded that morphine is reliably absorbed
into the systemic circulation when administered rectally to
an extent at least that of oral morphine. When oral therapy
is not an option, controlled release products are particularly
suited for rectal maintenance therapy. Similar observations
were found with opioids like oxycodone and methacodoen
and also with non steroidal anti inflammatory drugs like
raproxem, diclofenac and ibuprofen.47
CONCLUSION:
Rectal drug delivery with the advantages of enhancement in
drug absorption with enhancers, stabilizing proteins and
peptides and partial avoidance of first pass metabolism will
undoubtedly be a pioneer in formulation of various
challenging compounds. From the safety point of view it
will be important to recognize the time window needed for
absorption
enhancement,
problems
related
to
pharmacokinetics and pharmacodynamics of the enhancer
and recovery with respect to possible cellular damage.
ABBREVIATIONS:
CMZ: cefmetazole, 5MSA: 5-methoxysalicylate, TCA
cycle: tri carboxylic acid cycle, EDTA: ethylene diamine
tetra acetic acid, EGTA: ethylene glycol tetra acetic acid,
K+-ATPase:
sodium
potassium
adenosine
Na+,
triphosphatase, DEM: diethyl maleate, AUC: area under
curve.
ACKNOWLEDGEMENTS:
Authors are thankful to Chalapathi Institute of
Pharmaceutical Sciences and Ms. K. Lakshmi Prasanna for
providing the facilities to bring out this review.
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