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Rectal Drug Administration
Abstract
Rectal administration may be a very useful route for a variety of drugs in horses that are unwilling or unable to be medicated orally or parenterally. Metoclopramide and cisapride are both well absorbed rectally, and this may be used to advantage in cases of post-operative ileus and anterior enteritis. Nonsteroidal anti-inflammatory drugs are variably, but usually well absorbed rectally, thereby reducing the risk of gastrointestinal ulceration. Diazepam, theophylline and ketamine are rapidly and well absorbed from the rectum, which may be very useful when medicating foals or unhandled young horses. Most of the drugs discussed are available in rectal formulations (suppositories or microenemas) for humans, eliminating the need for veterinarians to experiment with base formulations. Various studies report the use of higher than normal doses when drugs are given rectally, to compensate for the often lower bioavailability when compared with oral or parenteral administration. There is very little data on the pharmacokinetics and recommended doses of drugs that may be administered rectally to horses, and caution must be taken when extrapolating from human and laboratory animal data. Despite this, the convenience and safety may well make up for the lower and variable bioavailability of drugs administered rectally.
Six healthy mares ranging in age from 6 to 12 years and weighing from 415 to 540 kg were used to determine the rectal bioavailability of ketoprofen. For the rectal administration, three different formulations, each containing 1 g of ketoprofen, were administered in a fatty and a hydrophilic suppository base and as a liquid suspension. An average elimination half-life of 1.3 h (+/-1.2) was found. The average value for the total plasma clearance (ClT) was 131.9mL/ min.kg (range 95-183.5). The volume of distribution Vd(area) was 255 mL/kg and the mean residence time (MRT) value was 0.47 h. After rectal administration, the mean maximal plasma ketoprofen concentrations were 1.6(+/-0.8), 1.1(+/-0.7) and 1.6(+/-0.2) micrograms/mL for the fatty suppository, the hydrophilic suppository and the liquid suspension respectively. The absolute bioavailability of ketoprofen in horses after rectal administration of the three formulations was relatively low, with a large interindividual variability (24.5 +/- 9.5%, 28.7 +/- 18% and 31.3 +/- 6.8% for the fatty suppository, the hydrophilic suppository and the liquid suspension respectively). These values were not significantly different (P = 0.05; Friedman test). Despite the low rectal bioavailability obtained in this study, there was some evidence for the clinical effectiveness of the rectal formulations.
Ketoprofen (KTP) is a chiral non-steroidal anti-inflammatory drug (NSAID) of the propionic acid class, approved by the FDA for the allevation of pain associated with musculoskeletal disorders in horses. The present study was designed to examine the bioavailability of ketoprofen enantiomers after rectal administration of the racemate to healthy horses. One gram of racemic ketoprofen was injected intravenously and administered rectally as a fat based suppository in a cross-over design study (n = 4). Blood samples were analysed for KTP enantiomers using HPLC. After IV administration, the S(+) enantiomer concentrations in plasma were higher than the R(-) enantiomer concentrations and the AUC(0-12 h) for the S(+) enantiomer was significantly higher than for the R(-) enantiomer. Following rectal administration C(max) and AUC(0-12 h) were significantly higher for the S(+) than for the R(-) enantiomer. Bioavailability after rectal administration was low. Since there was no significant difference in bioavailability between the two enantiomers, it is assumed that no pre-systemic inversion from R(-) to S(+) occurred after rectal administration of racemic KTP to horses.
Part I of this article, which appeared in the previous issue of the Journal, covered general considerations, the physiology of the rectum, spreading of drugs into the colon, rectal absorption, partial avoidance of first-pass elimination, rate-controlled rectal delivery of drugs, irritation of the rectal mucosa and clinical applications of rectal administration, and discussed centrally acting drugs. In Part II, this discussion is extended to drugs which act peripherally and to methods of enhancing rectal drug absorption. The overall summary appeared in Part I.
Hanna, R.M., Borchard, R.E. & Schmidt, S.L. Pharmacokinetics of ketamine HC1 and metabolite I in the cat: a comparison of i.v., i.m., and rectal administration. J. vet. Pharmacol. Therap. 11, 84–93.
Ketamine HC1 [2‐(o‐chlorophenyl)‐2‐(methylamino) cyclohexanone HC1] concentrations in whole blood were used to study the pharmacokinetics of i.v., i.m., and rectal administrations, at a dose of 25 mg/kg, in normal domestic cats. Absorption was rapid with both the i.m. and rectal routes. Systemic availability was 51% (SEM 10) for the i.m. dose and 43.5% (SEM 6.1) for the rectal dose. The first‐pass effect had a minimal influence on the metabolism of ketamine HC1 administered rectally. The elimination rate constant (β) of the drug was statistically similar in the i.v., i.m., and rectal groups, at a 95% level of significance ( P < 0.05). At the dosage rates studied, ketamine HC1 produced an anesthetic effect in the cat following i.v., i.m. and rectal administration.
The pharmacokinetics of midazolam were investigated following intravenous and intramuscular administration of 0.5 mg of midazolam hydrochloride/kg of body weight to five healthy mixed-breed dogs. One dog also received the same dose of midazolam by oral and rectal routes. The disposition of midazolam following intravenous administration was characterized by very rapid and relatively extensive distribution followed by rapid elimination. Mean (+/- SD) apparent volume of distribution was 3.0 +/- 0.9 l/kg, mean elimination half-life was 77 +/- 18 min, and clearance was 27 +/- 3 ml/kg/min. Following intramuscular administration, absorption was rapid and complete. A mean peak midazolam concentration of 549 +/- 121 ng/ml was reached within 15 min, and systemic availability was over 90% in each dog. Oral administration to one dog resulted in peak midazolam concentrations within 10 min and a systemic availability of 69%. Rectal administration to the same dog yielded very low systemic availability. Midazolam was extensively bound to canine plasma proteins, with the unbound fraction representing less than 4% of the total plasma midazolam concentration. Plasma samples were also assayed for the presence of the major metabolites, 1-OH and 4-OH midazolam. Neither metabolite were detected, probably as a result of rapid elimination of these compounds by hepatic glucuronidation. Behavioral responses to administration of midazolam included initial signs of profound weakness, ataxia and transient agitation followed by a period of quiesence. A normal behavior pattern returned within 2 h of midazolam administration.
The efficacy of ibuprofen with scheduled administration, starting preoperatively, for postoperative pain was studied in 128 boys and girls, 4 to 12 yr old, having elective surgery. In a double blind placebo-controlled study, rectal ibuprofen (40 mg.kg-1.day-1 in divided doses) or placebo was given for up to three days. For two hours after surgery heart rate, blood pressure and respiratory rate were recorded every 15 min together with sedation scores and pain scores, as assessed by an observer and the patient. Morphine was given to all children, 0.1 mg.kg-1 iv or 0.15 mg.kg-1 im according to clinical needs. Every morning on the ward the patients were interviewed about the efficacy of the analgesic treatment. All unwanted effects were registered. In the recovery room the heart rate was lower (P less than 0.05) and the patient's pain scores were less (P less than 0.05) in the ibuprofen group. After orthopaedic operations children needed more opioid than after ophthalmic or general surgical procedures (P less than 0.001). However, after all operations the need for additional morphine was less in the recovery room (P less than 0.05), during the day of operation (P less than 0.01) and during the three-day study period (P less than 0.01) in children receiving ibuprofen. On the day of operation the analgesic therapy was considered to be good or very good by 44/53 and 32/49 of the children in ibuprofen and placebo groups, respectively (P less than 0.05). Later, their assessments did not differ.(ABSTRACT TRUNCATED AT 250 WORDS)
Generally, oral administration is the route of choice in the daily practice of pharmacotherapy. However, in some circumstances this is impractical or even impossible (during nausea and vomiting or convulsions, in uncooperative patients and before surgery). In these cases, the rectal route may represent a practical alternative and rectal administration is now well accepted for delivering, for example, anticonvulsants, non-narcotic and narcotic analgesics, theophylline, antiemetics and antibacterial agents, and for inducing anaesthesia in children. It may also represent an interesting alternative to intravenous or other injection routes of drug administration. The rate and extent of rectal drug absorption are often lower than with oral absorption, possibly an inherent factor owing to the relatively small surface area available for drug uptake. In addition, the composition of the rectal formulation (solid vs liquid, nature of the suppository base) appears to be an important factor in the absorption process by determining the pattern of drug release. This relation between formulation and drug uptake has been clearly demonstrated for drugs like diazepam, paracetamol (acetaminophen), indomethacin, methadone and diflunisal. Coadministration of absorption-promoting agents (surfactants, sodium salicylate, enamines) represents another approach towards manipulating rectal drug absorption, although this concept requires further research concerning both efficacy and safety. For a number of drugs the extent of rectal absorption has been reported to exceed oral values, which may reflect partial avoidance of hepatic first-pass metabolism after rectal delivery. This phenomenon has been reported for morphine, metoclopramide, ergotamine, lidocaine (lignocaine) and propranolol. Rectal drug delivery in a site- and rate-controlled manner using osmotic pumps or hydrogel formulations may provide opportunities for manipulating systemic drug concentrations and drug effects. The extent of first-pass metabolism may be influenced (lidocaine), depending on the site of drug administration in the rectum. The rate of delivery may determine systemic drug action and side effects (nifedipine), and it may affect the local action of concurrently administered absorption promoters on drug uptake (cefoxitin). Local irritation is increasingly being acknowledged as a possible complication of rectal drug therapy. Long term medication with rectal ergotamine and acetylsalicylic acid, for example, may result in rectal ulceration, and irritation after a single administration of several drugs and formulations has been described. The assessment of tolerability and safety is imperative in the design of rectal formulations. Recent studies corroborate the clinical relevance of rectal drug therapy, and the value of the rectal route as an alternative to parenteral administration has been assessed for several drugs, e.g. diazepam, midazolam, morphine and diclofenac.(ABSTRACT TRUNCATED AT 400 WORDS)
Chloroquine administered as a rectal suppository is resorbed both in rabbits and human volunteers. Although the chloroquine blood level in rabbit is proportional to the dose investigated, the human rectal mucosa has a limited absorption capacity of chloroquine being saturated at 15 mg/kg dose. In spite of this saturation character the chloroquine applied as rectal suppository may be a suitable formulation to treat or prevent the malarial infection for persons unable to take the drug perorally, e.g. children, or unconscious adults, or persons suffering with GI complaints after swallowing the chloroquine tablet.
In order to obtain an effective alternative to parenteral administration of several cephalosporins, experiments were carried out in rabbits by rectal route. The suppositories of cefotaxime (CTX), ceftazidime (CAZ) and cefoxitin (CFX) in association with surface active sodium lauryl sulfate (SLS), release the antibiotic for absorption. Based on the positive results of the comparative plasmatic levels, this dosage appears to be applicable to humans too.
To compare the effectiveness of propofol given intravenously and rectally, ten piglets received propofol intravenously. On the next day, the same piglets and five other piglets were given suppositories containing propofol. Serial blood samples were collected for the analysis of propofol plasma concentration. The time course of the total plasma drug concentration was fitted into a bi-exponential function using a least square fitting regression computer programme. The volume of distribution was 2.5-2.8 l.kg-1, mean elimination half-life, 23.9 min and mean clearance 0.08 l.kg-1.min-1. The mean bioavailability by the rectal route was low. In contrast to the intravenously administered propofol, none of the piglets slept when given propofol rectally, reflecting the extremely low plasma propofol concentration. In veterinary medicine, propofol would seem to be clinically valuable for inducing intravenous anaesthesia, but would be ineffective when given rectally. The findings indicate that with the dosage forms used here, propofol would be clinically ineffective if given rectally to human infants and children.
Erythromycin pharmacokinetics was studied in neonates (less than 1 month), infants (1-12 months) and other children (1-12 years) after the drug rectal and intravenous administration. The areas under the erythromycin serum concentration-time curves (AUC) were practically independent on children's age following the intravenous drug administration, but not its rectal administration. There was a distinct age dependency of the AUC parameter in the latter case. The increase of children's age was resulted in enhancement of the erythromycin total clearance, reduction of the steady-state volume of distribution and of the mean residence time. The extent of absolute bioavailability of rectally administered erythromycin was increased from 28 per cent in neonates to 36 per cent in infants and to 54 per cent in children greater than 1 year. Alteration of the mean absorption time parameter was reflected the delayed absorption of erythromycin in neonates.
To determine the feasibility and effects of preanesthetic rectal famotidine on gastric fluid pH and volume in pediatric patients.
Randomized, prospective, double-blind, controlled study.
Operating room at a medical center.
Eighty patients undergoing minor surgery under general anesthesia randomly allocated to one of two groups.
Thirty-four patients in Group 1 were given 0.5 mg/kg of diazepam rectally 30 to 120 minutes before anesthesia induction. Thirty-eight patients in Group 2 received 1 mg/kg of famotidine, a new histamine (H2) blocker, and 0.5 mg/kg of diazepam through the same route. Six patients in Group 1 and two patients in Group 2 were excluded from the study due to gastrointestinal (GI) disorders.
Patients with gastric pH less than 2.5 or volume of gastric contents greater than 0.4 ml/kg were considered to be at risk for pulmonary aspiration. Thirty-five (92%) of the Group 2 patients had gastric contents with pH greater than 2.5 and gastric volume less than or equal to 0.4 ml/kg. Only 13 (38%) of the patients in Group 1 had similar gastric pH and volume. Rectal administration did not cause the children pain, and no anorectal problems of famotidine were detected.
Famotidine 1.0 mg/kg administered rectally 30 minutes prior to general anesthesia appears to result in a satisfactory increase in gastric pH.