rectal drug administration

RECTAL DRUG ADMINISTRATION

Christine King BVSc, MACVSc, MVetClinStud

Some would say that the rectum is a grossly under-utilized resource in equine practice. For years we have probed its depths in search of information regarding the pelvic or abdominal organs, while failing to appreciate its capacious absorptive area and ready accessibility. Human medical practitioners have been much more ready to advise their patients to "shove it up your ...", and, in fact, a vast amount of research has gone into investigating the rectal absorption profiles of many different drugs in humans. The rectal route is particularly useful in young children 29 whose "compliance characteristics" are in many ways similar to those of most veterinary patients.

The rectal route has many advan- tages over oral and parenteral routes of administration. For starters, iris simple, safe (that is, for the patient), and mini- mally invasive. Rectal administration is a viable alternative when (1) oral administration is not tolerated, such as when patients refuse to eat or be given oral medications, (2) oral medication is not advisable, for example, in neonates and in cases with oral or esophageal injuries or gastric ulceration, (3) the oral route is unavailable, such as in convulsing or anesthetized patients, and (4) gastrointestinal motility is altered, such as in cases of ileus and anterior enteritis, or in patients with delayed gastric emptying. The rectal environment is fairly constant with respect to

nous blood from the caudal part of the rectum flows into the caudal vena cava, 24,25 reducing the effect of hepatic first pass metabolism, which is the fate of many orally-administered drugs. 29 Several clinical trials in humans report similar efficacy and fewer side effects, such as nausea and vomiting, when rectal was compared with oral administration.29, 30 The extensive research and development that has gone into improving the reliability and efficacy of rectal formulations for humans pro- vides veterinary practitioners and re- searchers with a very good foundation for investigating this route in animals.

The drawbacks of the rectal route in veterinary practice include (1) variable and incomplete absorption of many drugs (also true for human patients 29, 3% (2) no control over patient compliance (human patients can be directed to retain a suppository for several hours if needed), (3) voluminous fecal produc- tion and frequent elimination in herbi- vores, and (4) the amount of drug needed for rectal administration often exceeds the parenteral dose, ag,a° increasing the volume and cost of medication. It may be advisable to evacuate the horse's rectum before administering drugs, but client compliance could prove difficult when dispensing medication for them to administer in this way.

Anatomy and physiology of the rec tum

The rectum in the horse is approxi- mately 30cm long. The cranial, or peri- toneal portion differs from the caudal, or retroperitoneal portion, in that, like the small colon, the cranial part of the rectum is covered by serosa and is attached by a continuation of the colonic mesentery (the mesocolon). The cau-

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structures by connective tissue and muscle. 25 The arterial supply to the rectum comes from the caudal mesenteric arteries (cranially) and the inter- naliliac, or pudendal arteries (caudally). Venous blood returns to the portal circulation via the caudal mesenteric vessels (cranially) or to the caudal vena cava via the internal iliac, or pudendal veins (caudally). 24, 25 The submucosa is ,yery abundant in the wall of the rectum and it is loosely attached to the muscular layer, such that the mucosa forms numerous folds when the rectum is empty. The caudal part of the rectum dilates to form the flask-shaped am- pul la recti, 2s which acts as a repository for feces.

Although the human colon absorbs water, sodium and chloride, and se- cretes potassium and bicarbonate ions, there is no significant absorption of water or electrolytes in the rectum. 2a The rectal mucosa in humans consists of one layer of columnar epithelial, goblet and endocrine cells. In the last 4- 5cm of the rectum there is a transition from columnar to stratified squamous epithelium, a9 Drugs may be absorbed across the epithelial cells or via the tight junctions between cells. In rats, the biphasic absorption profile of certain compounds led to the conclusion that rectally-administered drugs may be absorbed from two different sites - the rectum and the terminal colon, with absorption from the rectum being faster than from the colon, s This is also true in humans, although the amount of drug reaching the terminal colon depends on the volume of administered drug. 2a The venous route (portal circulation or caudal vena cava) depends on the site of drug absorption (cranial or caudal rectum), which therefore influences the

Volume 14, Number 10, 1994 521

degree to which the drug undergoes hepatic first pass metabolism. This metabolism can be considerable, such that certain drugs (for example, morphine 1 and codeine aa) can attain a higher peak serum concentration when given rectally than when taken orally.

Faetors affecting drug absorption Several factors can influence rec-

tal drug absorption; some can be con- trolled or harnessed while others present serious limitations to bioavailability.

Amount of drug administered If there are no limitations to ab-

sorption, there is a direct relationship between drug dosage and peak serum concentration, a9 Most drugs are absorbed along a diffusion gradient, a9 and there is some evidence that absorption is saturable for certain drugs (for example, chloroquine la and naproxen 3° in humans).

Amount of drug available Several factors can affect the

amount of drug that is available for absorption. Before being absorbed, the drug must be released from its base or vehicle and dissolved in the residual rectal fluid. The rate and extent of drug release varies with each drug and each base. zg,z° Bases may be aqueous solutions (or microenemas), hydrophilic substances such as polyethylene glycol and methylcellulose, or fatty substances such as triglycerides and waxes. 29,30 The absorption profiles of many com- monly used drugs give clear indica- tions that the choice of base is very important in optimizing rectal drug absorption. 29,z° After release from its base, the drug may (1) precipitate in the rectal fluid (as with methadoneZ9), (2) be metabolized or degraded in the rectal lumen by bacteria, proteolytic enzymes and mucosal cells, z9 (3) be adsorbed onto fecal material, or (4) be eliminated during defecation. The amount of drug available for absorption also depends on the stability of the

compound in the rectal environment, z9 Little is known about the influence

of fecal characteristics on drug avail- ability in horses. The volume, consis- tency, content, pH, enzymes and bacte- rial florain equine feces may all present a considerable barrier to drug absorption. Unless the rectum is evacuated before drug administration, the drug would likely be deposited directly into or onto feces, and virtually be lost. In horses with diarrhea (either physiologi- cal or pathological) the frequency of defecation, the increase in fecal volume, and the loss of anal sphincter tone would render this route of drug administration useless.

Absorptive area While the surface area of the rectal

mucosa is finite, the drug and its vehicle can migrate cranially and also be absorbed from the terminal colon, s'z°'z9 The absorptive area is dependent upon the spreading characteristics and the volume of the base, and the depth of insertion of the compound into the rectum. z9 For most drugs, the larger the volume of dissolved base-drug, the better the drug absorption. However, larger volumes (over 25ml) are not well re- tained in humans. 29

Time available for absorption Whereas human patients may be

directed to administer the drug after defecation and retain it for some hours, no such compliance is possible with animals. The retention time of rectally- administered drugs in animals may be very short as it is dependent on the frequency of fecal passage, which is considerably greater in horses than in dogs, cats or humans. Further, large drug volumes or irritant substances may stimulate early elimination. For these reasons, the rate of drug release from its base is an even more important factor in animals. Drugs dissolved in aqueous solutions are generally more rapidly and completely absorbed than with other bases, z9 which can be important when

medication is needed quickly (for example, theophylline for apnea or respi- ratory distress, 16 and diazepamfl ° ketamine 17 or barbiturate 2z for sedation or control of seizures). It may be surmised that horses would be less likely to expel a small volume of liquid than a solid suppository.

Blood flow Rectal blood flow may be de-

creased in shock and dehydration, and increased in conditions causing local inflammation. Studies have shown that rectal blood flow can be enhanced by the rectal administration of short-chain fatty acids, such as acetic, propionic and butyric acids. 2° Whether this effect can be used to improve rectal drug absorption remains to be determined.

Absorption characteristics The drug formulation affects rec-

tal absorption, as it does with oral administration, z9 In the rectum, drug absorption may be limited by the mucus layer, cell membranes, tight junctions between cells, cytoplasmic enzymes, tissue layers, and the walls of blood and lymph vessels. 29 Co-administration of absorption-promoting agents has been investigated for several drugs in humans. These absorption-enhancers include surfactants, sodium salicylate, enamines, lecithin and weak acids. 29 Their general effect is to alter mucosal permeability, thereby improving.drug uptake. However, this can also lead to compromise of mucosal integrity, local inflammation and poor patient accep- tance .29

The pH of the compound can also influence the absorption of certain drugs. Both the bioavailability and rate of absorption of morphine are increased when the pH of the base is increased from 4.5 to 7.4. 29

Age An age-dependent rectal absorp-

tion profile has been identified for erythromycin in children. Bioavailability

522 JOURNAL OF EQUINE VETERINARY SCIENCE

Table 1: Rectal absorption profiles of various drugs

DRUG BIOAVAILABILITY

SEDATIVES, ANTICONVULSANTS, ANESTHETIC DRUGS DIAZEPAM sol'n: ~80%

CLONAZEPAM complete

M IDAZOLAM complete

PHENOBARB -90% of IM

THIOPENTAL good

PROPOFOL poor KETAMINE good (4 4 %)

METHOHEXITAL 8 - 3 2 %

T-max

-10rain

rapid

-30min

4hrs

rapid

7 -1 5 min

ATROPINE 32% of IM 1 5-60min

41-88% of IM

67-91% of PO -55% complete

OPIATES MORPHINE

METHADONE PETHIDINE CODEINE

GASTROINTESTINAL DRUGS METOCLOPRAMIDE complete

CISAPRIDE good

FAMOTIDINE good

OMEPRAZOLE very good

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS PHENYLBUTAZONE 77% of oral KETOPROFEN very good

40-9Omin

~3hrs slow 25min

30-60min

~50rain

2-6hrs - l h r

COMMENTS

clinically effective; safe, no effect on rectal mucosa; abe. profile affected by base 10,29 alternative to diazepam; much individual variation in bioavailability 29 good premed, in children, need 2X IV dose for same effect PR29; very low bioavail, in dog 8 abe. profile affected by base; not suitable for acute treatment of epilepsy 29 good sedation & recovery after 25mg/kg PR 22 poorly absorbed in piglets 7 good premed, and post-op. analgesia in children17; 25mg/kg PR in cats -> suitable anesthesia 15 satisf, induction of anesthesia in 90% of patients, rapid recovery with 25mg/kg PR; much individual variation 29

low, variable absorption and systemic effect 29

sedation within 30min; abe. profile affected by type and pH of base - aqueous (alkaline)microenema best; no local irritation reported 1, 29 affected by base 29 not recommended for acute pain 14 affected by pH of base; can cause rectal irritation 29

aqueous microenema (- 0.25mg/kg PR) 29 signif, increased gastric emptying & amplitude of gastric contractions a t - 0.4mg/kg pR2e clinically effective in increasing gastric pH in 92% of patients at lmg/kg PR; no local problems reported 21 higher ulcer prevention activity than with oral administration; higher rate and extent of absorption PR 23

in 3 healthy men3O clinically effective; minimal effect


Table 1, cont inued

IBUPROFEN 88% of oral -1 hr DICLOFENAC very good 15-60min

INDOMETHACIN 37-112% of oral 10-30min

very good 2hrs

of base; abs. profile comparable with oral 30 clinically effective PR 18,30 abs. profile affected by base - hydrogel best; sustained release formul'n available; clinically effective12,3o clinically effective; rate affected by base; local irritation in 1 patient 30 2-2.5mg/kg PR as suppository in horses; detectable levels in urine after 1 hr 8

ANTIBIOTICS METRONIDAZOLE 70-80% 1-3hrs

34-49% of oral 1.5hrs

ERYTHROMYCIN -40% 1 hr

AMPICILLIN poor

POT.SULFA's incomplete slow

CEPHALOSPORINS good

base affects abs. profile - faster rate with aqueous sol'n but better bioav, with PEG base; recommend IV loading then PR q8hr 30 effective for acute gingivitis in Indian elephant at 15mg/kg PR q24hr for 10 days 13 15mg/kg PR in horses; mean peak serum conc. above 2pg/ml for 6hrs 11 similar bioavail, for oral, altho' faster absorption PR; 30 slower and lower abs. in very young children; 27 therapeutic drug level for several hours with - 4mg/kg pR3o poor rectal abs. even with co- admin, of cloxacillin and other synthetic penicillins; causes diarrhea and rectal irritation 30 clinically effective in resp. and urinary infections despite abs. profile 30 cefotaxime, ceftazidime, cefoxitin suppositories in rabbits 3

MISCELLANEOUS COMPOUNDS THEOPHYLLINE complete rapid

THIABENDAZOLE very good ~ 4hrs

PROGESTERONE good 1-6hrs

MAGNESIUM complete l Omin

affected by base (sol'n best); effective in treatment of apnea in neonates, and asthma 16,30 clinically effective; higher serum conc. than oral 4 with fatty suppository; much individual variation 30 MgCl2 raised serum Mg to normal range after PR admin, in hypoMg calves, of oral which failed to reach normal serum Mg even after 160min-

Bioavailability: percentage of drug absorbed systemically, generally compared with IV dosing (unless specified) T-max: time to maximum serum concentration of drug (generally greater than time to effect) PEG: polyethylene glycol All data refers to humans, unless specified (veterinary data are in italics); superscripts indicate reference numbers


was 28% in neonates (less than 1 month of age), 36% in infants (1-12 months of age) and 54% in children (1-12 years of age). 27 The rate of absorption was also lower in neonates. The reasons for these findirrgs were unclear, but could include differences in hepatic metabolism as well as local factors in the rectum.

Drug absorption data Most of the data available on rec-

tal drug absorption relates to experimental work in laboratory animals or clinical trials in humans. Very little information has been published on rectal absorption of drugs in veterinary practice. Table 1 summarizes data on the rectal absorption of some drugs that may be used in veterinary practice. With reference to equine practice, certain findings are worth elaborating upon. Long-term use, or abuse of nonsteroidal anti-inflammatory suppositories has been reported to cause anorectal ulceration in humans. In most cases, cessa- tion of treatment resulted in complete resolution of the condition. In a few cases, however, deep mucosal ulceration resulted in stenosis, which re- quired surgical intervention. 9,28,3°

Indomethacin has been given rectally to racehorses in an effort to pre- vent drug detection during pre- or post- race drug testing. In one study, detectable levels were found in the urine within one hour of rectal administration of two 100mg indomethacin suppositories, disproving the supposition that the rectal administration of drugs circumvents their detection. 8

A study of the pharmacokinetics of metronidazole in horses revealed that rectal administration resulted in a lower mean peak serum concentration than with oral medication, although the time to maximum serum concentration and the serum half-life were similar. 11 In this study, the mean peak serum concentration was 4.5+2.0 ktg/ml after rectal administration of metronidazole at 15mg/kg. Tablets were crushed, dis-

solved in about 40ml of tap water, and delivered into the rectum via a lubri- cated catheter, after partial evacuation of the rectum. The authors noted that the reported minimum inhibitory concentration (MIC) for 90% of Bacte- roides species was <2gg/ml, and the MIC for Clostridial species of animal origin was <4gg/ml. In this study, the serum metronidazole concentration was above 2p.g/ml 10 min after rectal administration, and remained above that level until 6 hours after administration. However, the serum concentration was only above 4gg/ml between 1 and 2 hours after administration. 11 A recom- mendation from human studies entailed an initial intravenous loading dose of 7mg/kg, followed by 14mg/kg as a suppository every 8 hours. 3°

S U M M A R Y

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 postoperative 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 medi- cating foals or unhandled young horses. Most of the drugs discussed are available in rectal formulations (suppositories or microenemas) for humans, elimi- nating the need for veterinarians to ex- periment with base formulations. Vari- ous 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.

R E F E R E N C E S

1. Babul N, Darke AC. Disposition of morphine and its glucuronide metabolites after oral and rectal administration: Evidence of route specificity. Clin Pharmacol Ther 1993;54:286-292.

2. Bacon JA, Bell MC, Miller JK, Ramsey N, Mueller FJ. Effect of magnesium administration route on plasma minerals in Holstein calves receiving either adequate or insufficient magnesium in their diets. J Dairy Sci 1990;73:470-473.

3. Bahia MF. Absorption of some cephalosporins by rectal route in rabbits. (Abstract) Boll Chim Farm 1991 ;130:128- 132.

4. Boken D J, Leon PA, Preheim LC. Treatment of Strongyloides stercoralis hyperinfection syndrome with thiabendazole administered per rectum. Clin Inf Dis 1992;16:123-126.

5. Bramer SL, Wientjes MG, Au JL. Absorption of 2',3'-dideoxyinosine from lower gastrointestinal tract in rats and kinetic evidence of different absorption rates in colon and rectum. Pharm Res 1993;10:763-770.

6. Court MH, Greenblatt DJ. Pharma- cokinetics and preliminary observations of behavioural changes following administration of midazolam to dogs. J vet Pharmacol Therap 1992; 15:343-350.

7. Cozanitis DA, Levonen K, Marvola M, Rosenberg PH, Sandholm M. A comparative study of intravenous and rectal administration of propofol in piglets. (Abstract) Acta Anaesthesiol Scand 1991 ;35:575-577.

8. Delbeke FT, Debackere M, Vynckier L. Disposition of human drug preparations in the horse. I. Rectally administered indomethacin. J vet Pharmacol Therap 1991;14:145-149.

9. D'Haens G, Breysem Y, Rutgeerts P, van Besien B, Geboes K, Ponette E. Proctitis and rectal stenosls induced by nonsteroidal anti-inflammatory suppositories. J Clin Gastroenterol 1993;17:207- 212.

10. Dieckmann RA: Rectal diazepam for prehospital pediatric status epilepticus. Ann Emerg Med 1994;23:216-224.

11. GarberJL, Brown MP, Gronwall RR, Merritt K. Pharmacokinetics of metroni-


dazole after rectal administration in horses. Am J Vet Res 1993;54:2060-2063.

12. Gillberg LE, Harsten AS, Stahl LB. Preoperative diclofenac sodium reduces postlaparoscopy pain. Can J Anaesth 1993;40:406-408.

13. Gulland FMD, Carwardine PC. Plasma metronidazole levels in an Indian elephant (Elephas maximus) after rectal administration. Vet Rec 1987; 120:18.

14. Hamunen K, Maunuksela EL, SeppalaT, Olkkola KT. Pharmacokinetics of i.v. and rectal pethidine in children undergoing ophthalmic surgery. Br J Anaesth 1993;71:823-826.

15. Hanna RM, Borchard RE, Schmidt SL. Pharmacokinetics of ketamine HCI and metabolite I in the cat: A comparison of i.v., i.m., and rectal administration. J vet Pharmacol Therap 1988; 11:84-93.

16. Karlsson MO, Thomson AH, McGovern EM, Chow P, Evans T J, Kelman AW. Population pharmacokinetics of rectal theophylline in neonates. Ther Drug Monit 1991 ;13:195-200.

17. Lin SM, Liu K, Tsai SK, Lee TY. Rectal ketamine versus intranasal ketamine as premedicant in children. (Abstract) Ma Tsui Hsueh Tsa Chi 1990;28:177-183.

18. Maunuksela EL, Ryhanen P, Janhunen L. Efficacy of rectal ibuprofen i n controlling postoperative pain in children.

Can J Anaesth 1992;39:226-230. 19. Minker E, Ivan J. Experimental and

clinicopharmacological study of rectal absorption of chloroquine. (Abstract) Acta Physiol Hungarica 1991 ;77:3-4.

20. Mortensen FV, Hessov I, Birke H, Korsgaard N, Nielsen H. Microcirculatory and trophic effects of short chain fatty acids in the human rectum after Hartmann's procedure. BrJSurg 1991;78:1208-1211.

21. Nishimura M, Nakano S, Ueyama H, Uchiyama A, Tashiro C. Effect of preanesthetic rectal famotidine on pH and volume of gastric contents in pediatric outpatients. J ClinAnesth 1991 ;3:207-210.

22. O'Brien JF, Falk JL, Carey BE, Malone LC. Rectal thiopental compared with intramuscular meperidine, pro- methazine, and chlorpromazine for pediatric sedation. Ann Emerg Med 1991 ;20:644-647.

23. Sastry MS, Diwan PV, Krishna DR. Comparative evaluation of ulcer prevention efficacy of orally, rectally and sublingually administered omeprazole in three acute gastric ulcer models in rats. Fundam Clin Pharmacol 1993;7:77-80.

24. Schummer A, Nickel R, Sack WO. The viscera of the domestic mammals. 2nd edition. Verlag Paul Parey, Berlin; 1979:113.

25. Sisson S, Grossman JD. The anatomy of the domestic animals. 4th

edition. W.B. Saunders Co. Philadelphia; 1953:432-435.

26. Stacher G, Granser GV, Bergmann H, Kugi A, Stacher-Janotta G, Hobart J. Slow gastric emptying induced by high fat content of meal accelerated by cisapride administered rectally. Dig Dis Sci 1991 ;36:1259-1265.

27. Stratchunsky LS, Nazarov AD, Firsov AA, Petrachenkova NA. Age dependence of erythromycin rectal bioavailability in children. Eur J Drug Metab Pharmacokinet 1991 ;3: 321-323.

28. van GossumA, Zalcman M,Adler M, Peny MO, Houben J J, Cremer M. Anorectal stenosis in patients with prolonged use of suppositories containing paracetamol and acetylsal icyl ic acid. Dig Dis Sci 1993;38:1970-1977.

29. van Hoogdalem E J, de Boer AG, Breimer DD. Pharmacokinetics of rectal drug administrat ion, part I: General considerations and clinical applications of centrally acting drugs. Clin Pharmacokinet 1991 ;21:11-26.

30. van Hoogdalem E J, de Boer AG, Briemer DD. Pharmacokinetics of rectal drug administration, part I1: Clinical applications of peripherally acting drugs, and conclusions. Clin Pharmacokinet 1991;21:110-128.

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rectal drug administration

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