Download DRUG ABSORPTION BY SUBLINGUAL AND RECTAL ROUTES

Br. J. Anaesth. (1984), 56,69
DRUG ABSORPTION BY SUBLINGUAL AND RECTAL ROUTES
A. G. D E BOER, L. G. J. D E LEEDE AND D. D. BREIMER
Rectal administration of drugs has been used since
Ancient times to produce local effects. In addition,
the rectal route may be used for systemic administration of drugs for the following reasons (De Boer ct
al., 1982):
(a) the presence of nausea and vomiting, or when the
patient is unconscious;
(b) the presence of disease of the upper gastrointestinal tract which affects absorption of drugs given
orally;
(c) an objectionable taste (a factor which may be
particularly important in children);
(d) the achievement of a rapid systemic effect by
giving a drug in a suitable solution (as an alternative
to parenteral administration);
(e) drug absorption may be easily discontinued in
the event of an accidental overdose;
(f) the rate of drug absorption is not influenced by
ingestion of food or the rate of gastric emptying;
(g) first-pass elimination of high clearance drugs
may be partly avoided;
(h) contact with digestive fluids of the upper gastrointestinal tract is avoided, thereby preventing
breakdown of some drugs.
The disadvantages associated with administration
of drugs rectally include:
(a) interruption of absorption by defaccation, which
may occur particularly with irritant drugs;
(b) the surface area of the rectum is far smaller for
absorption than that of the duodenum;
(c) the fluid contents of the rectum are much smaller
than those of the duodenum and this may produce
problems with dissolution of some drugs;
(d) degradation of some drugs by micro-organisms
may occur in the rectum;
(e) patient acceptability may be a problem, at least in
some countries.
A. G. D E BOER, FH.D., L. G. J. D E LEEDE, PH.D. (Department of
Pharmaceutical Technology and Biopharmacy); D. D. BREIMER,
PH.D. Department of Pharmacology and Pharmacotherapy); University of Leiden, P.O. Box 9502,2300 RA Leiden, The Netherlands.
RECTAL DRUG ABSORPTION
Physiology of the Rectum
The length of the human rectum is approximately
10-15cm and the circumference 15-35cm. Its
fluid contents have a pH of 7-8. Because villi are
absent, the surface area is small (200—400 cm2) compared with that of the small intestine: (200 m2)
(Wilson, 1962). The rectum is drained by three
veins: superior, middle and the inferior rectal veins
(fig-1).
The inferior and middle rectal veins drain the
lower part of the rectum, while the superior rectal
vein drains the upper part. Between these three
veins exist extensive anastomoses.
FIG. 1. Detailed diagram of the venous drainage of the human
rectum. 1 = Middel rectal vein; 2 = Tunica muscularis: stratum
longitudinale; 3 — Levator ani; 4 — Inferior rectal vein;
5-Sphincter ani ezternus; 6-Superior rectal vein; 7 and
8 - Submucous venous plexus; 9 = Skin; 10 = V. Marginalis with
subcutaneous plexus. (After Tondury, 1981; reproduced with
permission.)
© The Macmillan Press Ltd 1984
BRITISH JOURNAL OF ANAESTHESIA
70
Rectal drug formulations
Physiological facton influencing rectal drug absorption
Several drug formulations may be used rectally.
These comprise suppositories (suspensions and
emulsions), gelatine capsules (solutions and suspensions) and enemas (macro—100 ml or more—and
micro—1-20 ml— solutions and suspensions). The
technical and pharmaceutical aspects of these formulations have been reviewed extensively by Thoma
(1980).
The suspension suppository is the formulation
used most widely clinically and this type has been
the subject of extensive research in vitro (Crommelin, 1979; Schoonen, 1980) and in vivo (RuttenKingma, 1977; Moolenaar, 1979). Its release
characteristics are influenced by many pharmaceutical and physiological factors related to the active
drug, the suppository base and factors related to
rectal environment (De Blaey and Polderman,
1980). Although drugs may be absorbed rectally
from an aqueous solution faster than via the oral
route, in general, absorption is slower with nonaqueous formulations. A critical factor in rectal
absorption is the limited amount of water available
in the rectum for drug dissolution.
Two factors are of major importance with respect
to the venous drainage of the rectum and consequently the transport of absorbed drug into the
systemic circulation: site of absorption and direction
of blood flow. If the drug is absorbed in the upper
part of the rectum, it is transported to the portal
system and passes through the liver while, following
absorption in the lower rectum, the drug is
transported directly to the systemic circulation. In
general, this implies that hepatic first-pass elimination is avoided when a drug is administered in the
lower part of the rectum. However, a complicating
factor is that there is no precise anatomical division
between the area draining to the portal and that
draining to the systemic circulation, because of the
presence of anastomoses.
De Boer and colleagues (1979) have shown that,
with lignocaine, it is possible partly to avoid hepatic
first-pass elimination following rectal administration of the drug (fig. 2). On average, systemic
availability was increased by almost 100% following
rectal administration compared with the oral route
for the same dose. These results were reproducible
O03
40
80
160
240
Time (min)
320
400
480
FIG. 2. Plasma concentrations of lignocaine following 200mgi.v. (Q), 300 mg rectal ( • ) and 300 mg oral
(O) administration to subject G.M. (After De Boer et al., 1979; reproduced with permission.)
SUBLINGUAL AND RECTAL ABSORPTION
when repeated in the same subjects and it was
calculated that the mean fraction of the rectally
administered dose escaping hepatic first-pass elimination was 57%. Other high-clearance drugs, for
example salicylamide and propranolol, did not exhibit an increase in mean bioavailability with the
rectal route compared with oral administration (De
Boer, 1979; De Boer et al., 1983). However, it is
possible that incomplete rectal absorption may have
masked the "bypass" effect.
In rats, these three drugs (lignocaine,
salicylamide and propranolol), when given rectally,
exhibit a far greater systemic availability compared
with oral administration (De Boer, 1979; De Boer et
al., 1980; De Boer, Gubbens-Stibbe and Breimer
1981; De Boer etal., 1981).
Rectal gut-wall metabolism and metabolism by
micro-organisms in the rectal lumen may decrease
bioavailability, but there is very little information on
this, although gut-wall metabolism is known to be
very important in the upper part of the gastrointestinal tract for some drugs (Curry, D'Mello and
Mould, 1970; Rivera-Calimlin et al., 1971; Barr,
1972; Dollery and Davies, 1972; Conway et al.,
1973). Although this latter process is not likely to be
important in the rectal wall, metabolism by microorganisms may be significant for some drugs, especially when hydrolytic and reductivereactionsoccur
(Scheline, 1973). Unfortunately there is little information on this topic in the human.
Examples of Rectally Administered Drugs
Anaesthetics, premedication and hypnosedative agents
Relatively little is known regarding rectal drug
administration for anaesthetic purposes. In principle, most drugs which are used for anaesthetic
purposes can be used rectally in premedication. In
this respect, attention should be directed to the
elimination kinetics of the drug (short c. long elimination half-life), the absorption characteristics and
the formulation used in the rectum.
Thiopentone. Thiopentone is a very lipophilic
drug and distributes very rapidly into the brain and
other well-perfused tissues (Gillis, De Angelis and
Wynn, 1976). Rapid onset of sedative action has
been shown to occur following rectal administration
of the drug in aqueous suspension (Boyd and Singh,
1967; Burckart et al., 1980) and in a suppository
containing the sodium salt (Lindsay and Shepherd,
1969).
Burckart and colleagues (1980) found, in chil-
71
dren, that, following rectal administration of a suspension of 25 mg kg"1 the mean duration of sedation
was 2.75 h. They considered that rectal thiopentone
was an effective alternative to i.m. administration of
a sedative "cocktail" (pethidine, chlorpromazine
and promethazine) for sedating patients before performing CT-scans. Similar results were found following rectal administration of a suppository containing the sodium salt of thiopentone to children
(Burckart et al., 1980). A dose of 42.3mg/kg body
weight produced hypnosis or adequate sedation.
However, recovery took more than 24 h, which may
be explained by the half-life of the parent drug (8 h),
while that of the primary metabolite (pentobarbitone)is26h.
Methohexitone. Methohexitone is also a very
lipophilic drug. Rectal administration of its sodium
salt (10% aqueous solution) to children, undergoing
elective surgical procedures, resulted in satisfactory
premedication (Liu, Goudsouzian and Liu, 1980).
The recovery time following rectal administration of
25 mgkg"1 was not significantly different than that
after i.v. administration of 5 nig kg"1 (Liu, Goudsouzian and Liu, 1980). A major advantage of this
agent is that the elimination half-life is very short
(1.2 - 2.1 h) while that of thiopentone is much longer
(Breimer, 1977). This suggests that, theoretically,
the recovery time following administration of
methohexitone should be shorter than that following thiopentone.
Benzodiazepines. Diazepam is very well absorbed
rectally from water -ethanol and propylene
glycol-water-ethanol solutions and has been
shown to be effective in the treatment of acute
convulsions (Agurell et al., 1975; Knudsen, 1977;
Dulac et al., 1978; Langslet et al., 1978; Meberg et
al., 1978; Magnussen et al., 1979; Moolenaar et al.,
1980; Breimer, 1983).
Rectal administration of an aqueous solution of
flunitrazepam 0.07 mg kg"1 resulted in a satisfactory
premedication in more than 400 children aged between 1 month and 12 yr (Govaerts, 1980). However, Cano and colleagues (1977) found an absolute
bioavailability of only 50% following rectal administration of flunitrazepam in a suppository. The
mean absorption rates following oral administration
of a solution and a tablet and rectal administration of
a suppository were 1.8 (range 0.7-3.3), 1.9 (range
1.2-2.5) and 1.6 (range 0.7-2.5) min"1 respectively.
72
Clonazepam is absorbed very slowly following
rectal administration from a propylene glycolwater-ethanol solution (Dijkhuis, unpublished observations), wheras nitrazepam in the same type of
solution resulted in a rapid absorption and an average absolute bioavailability of 79% in healthy subjects (Jochemsen et al., 1981). In contrast, Caille
and colleagues (1983) studied the absorption of
lorazepam from a tablet following sublingual and
oral administration to 12 healthy volunteers. The
mean absorption half-lives for the sublingual and
the oral routes were 15 and 55min respectively.
During maintenance treatment the time to steadystate was approximately 3 days, which correlated
well with the value predicted from single-dose
studies. The mean maximum and mean steady-state
concentrations were independent of the formulation
used.
Etomidate. Although attempts have been made to
administer etomidate rectally, inadequate sedation
has followed, despite the use of several different
formulations (water; water-ethanol-propylene
glycol; PEG-water) (De Boer et al., 1983; unpublished results). It should be a suitable agent for rectal
administration for premedication or sedation, since
the drug has a relatively short elimination half-life of
4 h (De Ruiter et al., 1981).
Chloral hydrate. Simpson and Parrott (1980) administered chloral hydrate and chloral betaine orally
and rectally to healthy male volunteers. Rectal administration in suppositories (base: beeswax and
cocoa butter) resulted in recovery of smaller
amounts of trichloroacetic acid (the major metabolite) from urine than when both were administered
orally.
Breimer, Cox and Van Rossum (1973) administered chloral hydrate in various suppository bases
(estarine D and PEG 1540: PEG 6000 4:1; particle
size < 150 um) and in rectioles (PEG 300 and sesame
oil; particle size< lSO^m). The absorption rate,
measured as the rate of appearance of the active
metabolite (trichloroethanol) in blood was comparable for all formulations (peak times after
0.5—2 h). The extent of absorption was greater with
the PEG formulations. In comparison with the PEG
suppository, the mean relative availabilities were
61%, 84% and 60% for the estarine D suppository,
the PEG rectiole and sesame oil rectiole respectively.
BRITISH JOURNAL OF ANAESTHESIA
Analgesic drugs
Acetylsalicylic acid (ASA) and sodium salicylate
(SA). Rectal absorption of ASA and SA is influenced strongly by the type of formulation (Cacchilo
and Hassler, 1954; Samelius and Astrdm; 1958;
Coldwell et al., 1969; Parrott, 1971; Gibaldi and
Grundhofer, 1975; Superstine, Superstine and Penchas, 1978). Moolenaar, Oldenhof and colleagues
(1979) showed that the absorption of ASA may be as
fast rectally as with oral absorption, but the pH is a
critical factor in this respect. An aqueous microenema (20 ml; pH 4.0) gives the best results. For
SA, comparable plasma concentration-time curves
are obtained when SA is given either rectally in a
suppository
(cocoa butter, particle size
125-250 jim) or orally in a tablet (fig. 3).
Paracetamol. In contrast with ASA, the pH of a
micro-enema is not a critical factor in the absorption
of paracetamol. However, the amount of enema
used is very important and the volume should be
20 ml (Moolenaar, Olthof and Huizinga, 1979).
When suppositories are used, relatively small particle sizes promote more rapid absorption, although
absorption rate is still slower than from an enema
(Moolenaar, Schoonen et al., 1979).
Indomethacin. Absorption of indomethacin rectally seems to be comparable to that following oral
administration. Baker and colleagues (1979) found
no differences in clinical effects, plasma concentrations and AUC following oral and rectal administration. Kwan and colleagues (1976) found an absolute
bioavailability of 80% following rectal administration in a suppository.
Propionic acid derivatives and other analgesics.
The analgesics derived from propionic acid, for
example naproxen (Desager, Vanderbist and Harvengt, 1976), benoxaprofen (Jones et al., 1980) and
ketoprofen (Ishizaki et al., 1980) are all well absorbed rectally in healthy volunteers when administered in a suppository. The same is true for alclofenac (Roncucci et al., 1971; Van Ginneken,
1976) and diclofenac (Riess et al., 1978).
Narcotic analgesics
Narcotic analgesics are usually administered by
the i.v., i.m. or oral routes. However, severe pain is
often associated with nausea and vomiting, which
SUBLINGUAL AND RECTAL ABSORPTION
73
30
e
3.
20-
O
.
-
10-
-
•
—
_
-
-
*
•
*
*
.2
Q.
40
120
80
160
200
Time (min)
FIG . 3. Mean plasma concentrations of salicyclic acid after oral administration to seven volunteers of aspirin
500 mg in 200 ml (O) and after rectal administration of sodium salicylate 431 mg (particle size 125-250jnn
( • ) , and particle size < 20 fim (*)). (After Moolenaar et al., 1979; reproduced with permission.)
prohibit oral administration of drugs. The rectal leagues (1981) found a mean rectal availability of
route is therefore a suitable alternative, but unfortu- 44% following rectal administration in supnately few studies have been conducted in this area. positories. For oxymorphone Beaver and Feise
(1977) showed that rectal administration was as
Pentazocine, ketobemidone, oxymorphone and mor- effective in treatment of postoperative pain as was
phine. Beckett and colleagues (1970) found that i.m. administration. Plasma concentrations of morhigher doses of pentazocine were needed with sup- phine following rectal administration in a suppositpositories to produce plasma concentrations com- ory were too low to be effective (Iindahl, Olsson and
parable to those following oral administration. Thomson, 1981).
Simonis, Eichner and Ecker (1975) found that pain
relief in patients with moderate and severe pain was Drug acting on the respiratory system
obtained following rectal administration of pentTheophylline. Theophylline is frequently adazocine 50 or 100 mg given in suppositories. Al- ministered rectally in a suppository and with most of
though the authors provided no experimental evi- the formulations, bioavailability is lower than after
dence they suggested that 75% of the rectal adminis- oral administration (Bolme et al., 1979). Bolme and
tered dose entered the general circulation without colleagues (1979) compared theophylline enemas
passage through the liver. However, the use of with suppositories in young children (2 months to 4
pentazocine in suppositories was found to be less yr) with asthma. The administration of supeffective than i.m. injections, particularly in the positories resulted in a variable bioavailability
treatment of severe pain, and was slower in onset of (8-100%, mean 80%) and a mean absorption halfaction (Schenk, 1974; Copsidas and Ward- life of 43 min. In contrast, the enema was absorbed
McQuaid, 1979).
rapidly with a mean absorption half-life of 5.5 min,
Most narcotic analgesics have not been studied while bioavailability averaged 100%. Three-times
extensively with regard to rectal administration. daily enema administration (6-8mg/kg body
However, for ketobemidone, Anderson and col- weight) produced continuously therapeutic
74
BRITISH JOURNAL OF ANAESTHESIA
(8-20 ngml ') theophylline concentrations. The bioavailability was comparable to that with oral
administration of single solutions rectally produced administration (25%).
a therapeutic effect and reproducible plasma concentrations (Yunginger et al., 1966).
Cardioactive drugs
Constant plasma theophylline concentrations
Propranolol. Absorption of propranolol rectally
have been obtained in healthy volunteers by the was faster than following oral administration, while
continuous rectal infusion of a solution using an mean systemic availability following oral and rectal
osmotic delivery system (De Leede et al., 1981, administration was 33 and 40% respectively in the
1982). The steady-state theophylline plasma con- same subjects (De Boer and Breimer, 1980).
centrations could be predicted on the basis of the in
De Leede and colleagues (1983) administered
vitro release rate of the system (which was identical propranolol rectally to healthy volunteers at a conto that in vivo) and the clearance of the subject. The stant rate with an osmotic system for 24 h and
plasma concentration profile was not influenced by obtained constant plasma concentrations and a good
renewing the delivery system or by defaecation (fig. correlation between concentration and betablockade measured by the isoprenaline challenge
4).
test (fig. 5). The mean rectal bioavailability (33%)
Thiazinamium. Quarternary ammonium drugs was comparable to that found by De Boer and
exhibit poor absorption characteristics because Breimer (1980). A disadvantage of this route is that
the drug is irritating to the mucosa and therefore not
these compounds are ionized at all pH values.
Jonkman (Jonkman, 1977, 1979; Jonkman et al., suitable for long term administration rectally.
1979) administered thia7innmiiim orally and rectally
to healthy volunteers. Rectal administration in a BUCCAL AND SUBLINGUAL ADMINISTRATION OF
DRUGS
lipophilic (Whitepsol HI5) and hydrophilic (PEG)
base was associated with a bioavailability of 6%—of
Physiology of the Sublingual and BuccalArea
the same order of magnitude as with oral administra- Although the total buccal and sublingual area is
tion.
small (200 cm2) and has a pH of 6.2-7.4 (Danhof
and Breimer, 1978) the potential exists for rapid
Promethazine. Moolenaar and colleagues (1981) absorption of drugs since these areas are rich in
found that rectal absorption of promethazine from a blood and lymphatic vessels (Spence, 1942; Goldmicro-enema in healthy volunteers was fast, but that berg, 1961; Hollinshead, 1968); thus rapid systemic
action may be achieved by administering drugs
sublingually or buccally. An important advantage of
these routes is that the drug passes directly into the
systemic circulation. Thus, hepatic high-clearance
drugs, or drugs which are subject to presystemic
gut-wall metabolism or decomposition in the
gastrointestinal tract, or both, will exhibit higher
systemic availability following sublingual, compared with oral, administration.
An important disadvantage of these routes is the
maintenance of the drug in the buccal and sublingual area. This varies between subjects and is dependent upon the drug formulation, disintegration,
flow of saliva and rate of drug absorption.
12
24
36
48
60
72
84
96
Time (min)
FIG. 4. Plasma and saliva concentrations of theophylline after
rectal administration of an osmotic system (O, • ) . + — insertion of
the first system; $ —insertion of the second system;
•ir =• withdrawal of the second system, compared with a standard
oral solution (D). (After De Leede et al., 1982; reproduced with
permission.)
Sublingual and buccal formulations
Tablets are used almost exclusively for buccal and
sublingual drug administration. Large tablets are
inconvenient because of their physical size and
therefore only potent drugs are suitable for administration by these routes.
Solutions are used only for studies of buccal
SUBLINGUAL AND RECTAL ABSORPTION
75
1965). An advantage of both routes is that drug
absorption can be easily terminated.
Various models have been proposed to describe
20
the mechanism of absorption of drugs from these
16
areas (Beckett and Triggs, 1967; Dearden and Tomlinson, 1971; Ho and Higuchi, 1971; Vora, Higuchi
12
and Ho, 1972). In general, polar drugs are badly
absorbed; for example dindamycin (Taraszka,
8
1970) is absorbed extremely slowly or not at all from
4the buccal cavity. Drugs with a moderate lipophilicity are well absorbed (Beckett and Moffat, 1969,
0
1970), while drugs with a very high partition coeffi100
10
20
50
cient are too water-insoluble to achieve a sufficiently
1
Propranolol (ngml' )
high concentration in salivary fluids (Gibaldi and
Kanig, 1965). The pH of the buccal area is imporFIG. 5. PropranoloJ plasma concentrations o. effect (isoproterenol dose ratio) for each individual during i.v. (O) and tant for the absorption of acid or alkaline drugs
rectal ( • ) administration.
(Beckett and Moffat, 1969,1970), while membrane
storage seems to occur for lipophilic drugs such as
propranolol (Schurmann and Turner, 1977). In adabsorption (Beckett and Triggs, 1967), while a paste dition, binding of drugs to macromolecules in the
has also been used (Erdle et al., 1979). These two mouth interferes with drug absorption (Dearden
formulations spread throughout the whole mouth, and Tomlinson, 1971).
which increases the chance of early swallowing of
The buccal absorption test is a useful tool and easy
the drug.
to perform. It has been shown (Beckett and Triggs,
There has been little work on the development of 1967) that this test provides a better indication of the
optimum drug delivery systems designed for long- passage of drugs through biological membranes
than do simple partition or rate of partition between
term sublingual or buccal use.
water and organic solvents.
Physiological factors influencing sublingual and buccal
There are two routes of transport of absorbed
absorption
drug into the systemic circulation. Absorption of
Absorption is highly dependent on the residence drug occurs into capillaries, but also uptake into
time of the drug in the sublingual and buccal area lymph may be significant, as has been demonstrated
and this may vary considerably. In addition, bad by buccal administration of para-aminosalicylic acid
taste or irritation caused by the drug may lead to in rabbits (De Marco and Blomsnes, 1974).
voluntary expulsion or swallowing. The residence
Examples of Buccal and Sublingual Drugs
time of the drug used is dependent upon the formulation: a solution has a shorter residence time than a Cardioactive drugs
tablet. Saliva flow is important since it affects the
Nitroglycerin and isosorbide-dinitrate. Nitroglycerate of dissolution of the drug and, if the saliva flow rin (NG) is a standard example of a drug which is
is considerable, there is an increased likelihood that often administered buccally or sublingually. Both
part of the drug will be swallowed before absorp- NG and isosorbide are used with more or less suction. Therefore the patient must learn to adapt to cess in the treatment of angina pectoris, variant
these routes of administration in order to avoid angina, congestive heart failure, acute myocardal
sucking on the tablet, swallowing the drug before infarction and peripheral vascular diseases (Elabsorption and excessive salivation by the presence kayam and Aronow, 1982). To evaluate the
of drug in the mouth (Gibaldi and Kanig, 1965).
therapeutic efficacy of the buccal and sublingual
During sublingual administration, the patient is route the effects of acute and chronic administration
not allowed to eat, drink, talk, smoke or chew—all require consideration.
of which influence tablet disintegration and resi- Acute treatment. Sublingual administration is the
dence time of drug in the mouth. In buccal ad- route of choice when acute therapy is desired. Nitministration, the patient may talk but should avoid roglycerin is absorbed rapidly following sublingual
drinking, eating and so on (Gibaldi and Kanig, and buccal (Blumenthal et al., 1977) administration,
24
BRITISH JOURNAL OF ANAESTHESIA
76
resulting in early and relatively high peak plasma
concentrations (fig. 6) and consequently, a rapid
onset of action. However, the rate of the elimination
of nitroglycerin is also rapid. It is metabolized in rats
by glutathione organic nitrate reductase (Needleman, Lang and Johnston, 1972) in the liver and also
degraded rapidly (76% in 1 h) when incubated in rat
serum (Dicarlo and Megler, 1970).
Isosorbide-dinitrate is also absorbed very rapidly
following sublingual administration. Peak serum
concentrations are reached within lOmin (SporlRadun et al., 1980). The rate of elimination following i.v. administration is also rapid with the halflives of parent drug, 2- and 5-isosorbidemononitrate, being 30min, 1.8h and 7.6h (SporlRadunetal., 1980; Taylor etal., 1980) respectively.
Prophylactic and maintenance treatment. Following oral administration of both nitroglycerin
(Blumenthal et al., 1977) and isosorbide-dinitrate
(Taylor et al., 1980) substantially higher doses are
required to obtain plasma concentrations of the
parent drug which are comparable to those following sublingual or buccal administration. Nitroglyce-
rin 2.5 mg in a capsule (orally) is not effective compared with 0.3 mg administered in a tablet sublingually (Blumenthal et al., 1977).
These drugs are subject to considerable presystemic elimination following oral administration and
they are not effective unless relatively high doses are
given.
A plasma concentration profile similar to that
following high-dose oral administration is achieved
with nitroglycerin applied in an ointment
(Blumenthal et al., 1977). Also, satisfactory results
for continuous treatment have been shown following buccal administration of nitroglycerin in a sustained-release tablet (Greengart et al., 1983). Reduction in angina pectoris and increase in exercise
duration occurred for more than 5 h.
In summary, it would appear that sublingual and
buccal administration of nitroglycerin and isosorbate-dinitrate are effective in the acute treatment of
angina pectoris. However, this route is probably less
effective and acceptable in maintenance therapy,
since the patient is required to take sublingual or
buccal preparations frequently and maintain them
in situ. Oral administration is to preferred in mainte-
1.0
^
0.8-
0.6-
0.4-
0.2-
0.0
20
40
60
80
100
140
Time (min)
FlG. 6.
Plasma nitrngiynrin mTy^rHTatinne nftir nHminii^TUt*"" "f ° 0 3-Tngmihlingiml tahlrt ( i j j a ft S-mg
oral capsule (O) and application of an ointment containing nitroglycerin 16 mg (*). (After Blumenthal et al.,
1977; reproduced with permission.)
SUBLINGUAL AND RECTAL ABSORPTION
77
nance treatment with sustained-release dose forms, tions differed considerably (20min-3h) and the
but a major disadvantage of this route is the very mean absolute systemic availability up to 3 h was
substantial presystemic elimination. It seems, how- 31%.
ever, that the metabolites of both compounds also
Edge, Cooper and Morgan (1979) also found that
have some pharmacological activity and are longer- buprenorphine was effective in sublingual administacting (Stauch, Grewe and Nisscn, 1975). For a ration for the treatment of acute pain. The analgesic
detailed description of the pharmacological proper- onset time, duration of action and extent of indities and therapeutic use of both drugs, the reader is vidual variation are not measurably different when
referred to the recent review of Elkayam and buprenorphine is given either sublingually or parenAronow (1982).
terally for postoperative pain (McQuay et al., 1980).
The duration of analgesia is approximately 9 h following a sublingual tablet (0.4mg), which is comNifedipine. Nifedipine is a calcium entry blocker parable to that achieved by parenteral administraused in the treatment of certain types of angina tion of 0.3 mg (Bullingham et al., 1981). In a followpectoris and in hypertension. Following sublingual up study Bullingham and colleagues (1982) measadministration of a 10-mg tablet it was shown to ured plasma buprenorphine concentrations over a
produce dilatation of the forearm vessels (Robinson, period of 10 h after administration. The mean peak
Dobbs and Kelsey, 1980). The antihypertensive concentration occurred at 200 min (90-360min)
effect after sublingual administration of a 10-mg following doses of 0.4 and 0.8 mg sublingually
tablet to patients (three women and four men) with (tablets, see fig. 7). The ratio of the systemic avessential hypertension was found to last approxi- ailabilities of the 0.8-mg group to the 0.4-mg group
mately 3 h, while the onset of action was rapid. Peak was 1.8:1, while the absolute systemic availability
concentrations were achieved within 1 h (Thibon- was 55% for both groups. The uptake from the
nier, Bonnet and Carvol, 1980).
sublingual site did not increase after 5 h.
In summary, while buprenorphine may be adPropranolol. The buccal absorption of prop- ministered sublingually in the treatment of pain, the
ranolol has been studied in two male volunteers by rate of absorption is relatively slow (in comparison
Henry and colleagues (1980). They measured the with injection); therefore in acute situations the
decrease in propranolol concentrations of a 20-ml sublingual route may not be so effective. In contrast,
solution introduced and maintained in the buccal for maintenance therapy administration by the subcavity. Recovery was found to be dependent on pH lingual route seems to provide satisfactory results
(variation of 5.2-9.2) of the solution and varied for treatment of pain (Bullingham et al., 1981,
from 55.6 to 18.9% respectively. With a variation in 1982).
residence time of l-15min there was an accompanying variation in recovery time of 58.0-36.3%.
Phenazocine. Brown (1966) studied the buccal
In a similar study, Ohashi and Turner (1979) found absorption of phenazocine and found that a dose of
that the pH-dependent absorption of propranolol 5 mg (tablet) was as effective as 2 mg given i.m. to
from the buccal mucosa was 80%.
patients with pain after operation, while the results
were considerably better than those with the oral
preparation. In addition it was suggested that doses
Narcotic analgesic drugs
of 10 and 20 mg sublingually given two or three
Buprenorphine. Bupernorphine is a long-acting times in 24 h could maintain good analgesia in panarcotic analgesic, which exhibits a substantial first- tients with carcinoma and severe intractable pain
pass effect following oral administration, resulting over 24 h. This could not be obtained with oral
in large inter-individual variations in systemic av- administration of the drug (Brown, 1966).
ailability (Bullingham et al., 1981). Following sublingual administration of buprenorphine in tablets Hormones
to 15 patients undergoing total hip replacement, the
Oestrogens and methyltestosterone. Burnier and
initial rate of absorption was fast, but subsequently colleagues (1981) studied the sublingual absorption
diminished. Relatively low, but effective plasma of micronized 17 0-estradiol (E2, tablet 0.5 mg) in 10
concentrations were reached within 3 h (Bullingham postmenopausal women. With a single dose, a 26et al., 1981). The times of peak plasma concentra- fold increase in serum E2 occurred and a nine-fold
BRITISH JOURNAL OF ANAESTHESIA
78
1.0
0.8-
I
A
1/ ^
V
!
"\3
V
\
b^N
\ '
'
\ ^~*
0.4H
b
0.27P
1*
A
V ~L* all*
^ ^ ^ " ^ i> ^< rit i-t£
<y_u
J.J,J.
1/
0.0
200
400
Time (mm)
600
800
FIG. 7. Plasma concentrations of buprenorphine following i.v. administration of 0.3 mg(*), and sublingual
administration of a ublct containing 0.4 m g ( » ) and 0.8 mg(O). (After Bnllinghflm et al., 1982.)
increase in serum estrone (El) compared with endogenous concentrations. Concentrations of follicle
stimulating hormone (FSH) and luteinizing hormone (LH) decreased significantly within 6 h. With
a dose of 0.5 mg alternate nights, increased circulating concentrations of oestrogens were obtained.
Rapid absorption of a sublingual dose (micronized E2 2 mg) was found in hypogonadal women and
those with a normal cycle (Casper and Yen, 1981). A
nine to 41 -fold increase in basal E2 serum concentrations was observed within 30min. Because El was
the predominant circulating oestrogen it was concluded that the sublingual route is not ideal for E2
replacement.
Methyltestosterone is well absorbed sublingually
(Alkaly and colleagues, 1973). The systemic availability of methyltestosterone following oral doses of
25mg and 10 mg (tablets) and sublingual doses of
10 mg and 5 mg (linguets) relative to an oral solution
were 0.90, 0.95, 1.42 and 1.63 (corrected for dose
differences) respectively. The higher bioavailability
with the sublingual route probably results from
avoidance of liver metabolism.
analogues of vasopressin produce adequate
therapeutic effects when administered sublingually
as tablets (3 x30ngday~')- Greater doses were
needed than those with the intranasal route of administration (Laczi et al., 1980).
Oxytocin. Buccal administration of oxytocin from
linguets has been used for the induction of labour
(Miller, 1974). Induction was successful in 84% of
patients. The doses ranged from 200 to 800 units
with 26 patients responding to 1000 units of less. In
most instances labour was induced in less than 7 h.
Although this method is simple and convenient, a
major complication seems to be an increased occurrence of postpartum haemorrhage.
Other drugs
Ergotamine. The absorption of ergotamine across
the buccal mucosa appears to be a passive process,
pH-dependent, but independent of ergotamine concentrations and not influenced by simultaneous administration of caffeine. As a result of the low
aqueous solubility of ergotamine it is unlikely that
therapeutic amounts of the drug are absorbed across
Vasopressin analogues. It has been shown that the buccal mucosa (Sutherland et al., 1974).
SUBLINGUAL AND RECTAL ABSORPTION
CONCLUSION
Although the rectal and sublingual routes are not
used frequently for administration of drugs, both
routes may serve as alternatives to oral and parenteral administration. Each route has different limitations which decrease general applicability for drug
administration.
The disadvantages of the rectal route include
interruption of absorption by defaecation and lack
of patient acceptability. The mechanism of drug
absorption from the rectum is probably similar to
that from the small intestine, despite considerable
differences in physiological conditions (e.g. pH,
fluid content). Absorption may be extremely fast
with solutions. The rectal route is suitable for shortand long-term drug delivery and it is possible partly
to avoid hepatic first-pass elimination.
The sublingual and buccal routes of administration are useful when fast action is desired with
potent drugs. In addition, first-pass elimination
(gut-lumen, gut-wall and hepatic) is avoided. Prolonged residence in the mouth can limit usefulness
because of patient intolerance, and for long-term
drug administration this route is not convenient
when conventional formulations are used.
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