European Review for Medical and Pharmacological Sciences 2007; 11: 165-170 Suppositories in anal disorders: a review

P.J. GUPTA

Gupta Nursing Home, Laxminagar, NAGPUR (India)

Abstract. – Introduction: Drug treat- creams are the two main modes of administration ment for various ano-rectal conditions has of drugs through the rectum2. been known since ancient times. Supposito- Suppositories are a medicated solid dosage ries are one of the very feasible modes of ad- ministration for . form intended for insertion into the body orifices. Materials and Methods: Medline (1950- The term suppositories have its origin in Latin 2006) was searched for all published reports and means, “to place under”. It is thought that about suppositories. This study sum up vari- suppositories were first used in nursing facilities ous suppositories used in proctological prac- to be administered to elderly patients who were tice, which either are in vogue and have been not capable of receiving through used with a proven degree of success, or sup- more traditional delivery systems3. positories which are described in the literature but are no more in use. This study attempts to In humans the rectum comprises the last 12-19 highlight the advantages and drawbacks of cm of the colon and the rectal epithelium is each of them. formed by a single layer of columnar or cuboidal Results: Over 30 different types of ingredi- cells and goblets cells; its surface area is about ents have been found which are used singly or 200-400 cm2. The absorbing surface area of the in conjugation in suppositories formulation. rectum is considerably smaller than that of the While there are only few reports of adverse re- action following use of suppositories like rec- small intestine, as the former lack villi and mi- tal ulcer, rectal stricture and stenosis, the crovilli. However, the epithelium in the rectum overall acceptance of this mode of medication and the upper intestinal tract are histologically is good. similar, giving them comparable abilities to ab- Conclusion: Suppositories offer to the pa- sorb drugs. The veins of the rectum comprise the tients an option that is less invasive and less superior hemorrhoidal vein, which drains into the discomforting. Suppositories could well be inferior mesenteric and portal system, and the looked as a convenient drug delivery system in patients having ano-rectal symptoms. middle and inferior hemorrhoidal veins, which enter the systemic venous circulation via the in- Key Words: ternal iliac veins. However, it is a little known Suppositories, Anal, Rectum, Proctology, Ano-rectal fact that the inferior and middle hemorrhoidal disorder. veins bypass the liver and do not undergo first- pass metabolism. Therefore, the drugs delivered through suppositories to the lower and middle hemorrhoidal veins are absorbed rapidly and ef- fectively. The rectum is an interesting area for drug absorption because it is not buffered and Introduction has a neutral pH. It also has a very little enzy- matic activity, thus enzymatic degradation does Drugs or medications are administered not occur. The rectal mucus is more capable of through a variety of routs, the most common be- tolerating various drug related irritations than the ing the oral and parenteral route. While rectal gastric mucosa2. route is less commonly used in routine practice, The ano-rectal physiology provides a suffi- in proctological disorders it is being used effec- ciently adequate surface area for drug absorption. tively since long1. Drugs mixed with various ad- The surface area is also permeable to non-ion- juvant and administered through the rectal route ized drugs. Suppositories formulations are rather do provide satisfactory pharmacokinetics with efficient in variety of different bases to increase acceptable local tolerance. Suppositories and absorption and reduce complications4. The osmo-

Corresponding Author: Pravin J. Gupta, MS; e-mail: [email protected] 165 P.J. Gupta sis process allows the drug to transfer from the Suppositories Containing Steroids vehicle in the suppositories across the membrane Several glucocorticosteroids are used in rec- of the rectum, and into the hemorrhoidal veins. tal suppositories. They include hydrocortisone The higher the concentration and the greater the and its derivatives, diflucortolone valerate and solubility, the more efficient is the transfer of prednisolone8. The steroids act as decongestant, medication5. anti-inflammatory and anti pruritic agents and Several local host factors may influence ab- in doing so they eliminate inflammation and sorption in the rectum: the mucus layer, the vari- mucus discharge. It has been postulated that the able volume of rectal fluid, the basal cell mem- analgesic effect of the local anesthetics is ap- brane, the tight junctions and the intracellular parently prolonged by an increase in the thresh- compartments may each constitute local barriers old for pain by the anti-inflammatory effect of to drug absorption; depending on histological steroids9. factors and on the molecular structure of the ad- ministered drug. Suppositories Containing Astringents Suppositories come in various sizes and The astringent causes the cells of the anal skin shapes, which facilitates their insertion and re- to clump thereby drying the skin, which gives re- tention in the cavity. Adult rectal suppositories lief from burning and itching. weighed about 2 g while those for children are Some common astringents that are used in- about half that weight. clude Hamamelis water, which is a mild astrin- gent prepared from twigs of Hamamelis virgini- ana. It helps in relief from the hemorrhoidal itch. Zinc oxide 5 to 25% prevents the irritation at Materials and Methods the perianal area by forming a physical barrier on the skin that prevents the contact of the irritated Medline (1950-2006) was searched for all skin with aggravating liquid or stool from the published reports using the key words “Supposi- rectum. tories, anal, , rectum and proctol- ogy”. This study sum up various suppositories Vasoconstrictors in Suppositories used in proctological practice, which either are in Hemorrhoidal cushions contain swollen blood vogue and have been used with a proven degree vessels. The vasoconstricting agents can help in of success, or suppositories which are described relieving symptoms of hemorrhoids. On applica- in the literature but are no more in use. The study tion, these drugs cause the blood vessels to attempts to highlight the advantages and draw- shrink, thereby reducing hemorrhoidal conges- backs of each of them. The suppositories used tion. These products additionally contain mild for inflammatory and irritable bowel disease, form of anesthetic, which helps in relieving pain malignancy and systemic infection have been ex- and itching10. cluded. The commonly used vasoconstrictors are: Ephedrine sulfate 0.1 to 1.25%, Epinephrine Suppositories Containing 0.005 to 0.01% and Phenylephrine o.25%. Local Anesthetics agents The local anesthetics act by numbing the nerve Protectants in Suppositories endings and provide temporary relief from pain Passing hard and dry stool is the most traumat- and itching. These act by causing a reversible ic experience in patients having anal pathology block to conduction in the sensory nerves. These as it results in tearing of the skin around the are well absorbed from the mucus membrane and anus, as also in tearing and cracking which ends used as surface anesthetics6. These provide good in bleeding. Again, when this tender skin comes relief from discomfort encountered in cases of in contact with liquid or stool, it causes the skin strangulated hemorrhoids, fissures and perianal to further itch and burn. hematomas7. Protectants, when applied in the form of sup- Some commonly used local anesthetics are: positories, form a physical barrier on the skin 5 to 20%, 2 to 5%, Cin- and results in reducing the pain quotient and the chocaine, Dibucaine 0.25% to 1%, Dyclonine pruritus. These also protect the broken skin from 0.5% to 1%, Pramoxine 1% and Tetracain 0.5 to coming in contact with offending particles in the 5%. stool.

166 Suppositories in anal disorders: a review

While a variety of protectants are used in sup- wound area and thereby stimulates regeneration positories, a few commonly used are: Aluminium and re-epithelization process. It also has a an- hydroxide gel11, Glycerin, Lanolin, Aloe vera, timicrobial property which guards against infec- White petrolatum, Zinc oxide and Calamine. tion and prevents inflammation. Policresulen also has astringent property and thus it suppresses Use of Antiseptics in Suppositories oozing13. Being a highly contaminated area, the anal and perianal skin are susceptible to variety of organ- Other Ingredients in Suppositories isms, which can lodge there either from the ad- Imiquimod containing suppositories have been joining area or from the contaminated stool. The successfully used to prevent recurrence of anal chances of contamination further increase when condylomata14. Trimebutine, an anal sphincter re- the skin gets bruised during defecation. laxant, has been used to relieve post hemor- Antiseptics are used to keep the area clean and rhoidectomy pain15. Ketoprofen suppositories to prevent infection. The commonly incorporated were recommended in patients after anal antiseptics include: Benzalkonium chloride, surgery16. Boric acid and Framycetine sulphate. A sedative cryotherapy was being used with the intention of producing tissue hypothermia, Use of Keratolytics in Suppositories giving cool numbing effect over the Certain chemicals cause the outer layers of hemorrhoids17. Promethazine suppositories were skin and other tissues to disintegrate when ap- proposed for hemorrhoidal complications while plied. They eventually help in better penetration trichloroacetic acid was used for the treatment of in the tissues of other medications contained in anal fissures18. A compound Carraghenates sup- the suppositories to bring quicker relief. The two positories has been shown to be useful in the commonly used keratolytics are: Aluminium treatment of mixed hemorrhoids19. chlorhydroxy allantoinate 0.2 to 2% and Resorci- Few old references have described use of nol 1 to 3%. Roinal20, Glycofuranoside derivatives21, Indacine22, Prothanon23, Rhubarb and Aloe24, Use of in Suppositories Phenylindanedione25, Proctoglivenol in supposi- Calcium dobesilate is a veno-tonic drug, tories forms26. However, they are no more in use. which is widely prescribed for three main indica- The various ingredients in suppositories form tions: chronic venous disease, diabetic retinopa- with their use; adverse effects and contraindica- thy and the symptoms of hemorrhoidal attack12. tions for their use have been elaborated in Tables The drug acts on the endothelial layer and base- I and II. ment membrane of the blood capillaries. It re- duces capillary hyperpermeability by increasing Insertion Technique of Suppositories the activity of endothelial nitric oxide synthase in It has been suggested that the suppositories vascular endothelial cells, leading to an increase should be inserted with the patient lying on the in nitric oxide synthesis. Along with Calcium left lateral side with the right knee bent. The dobesilate, the suppositories usually contain local suppositories should be dipped in water before anesthetic, steroid and astringent in addition use, which facilitates the easy insertion of the [Smuth suppositories from Aristo Pharmaceuti- suppositories. It should be kept in cold water or cals, Mumbai, India]. refrigerator for half an hour before use if the suppositories are too soft to be inserted, espe- Suppositories Containing Policresulen cially during warm weather. Emptying of bow- Policresulen is a polymolecular organic acid. el should be avoided for at least an hour after It coagulates necrotic or pathogenically altered insertion of the suppositories to allow it to be tissue in anorectal disorder and promotes desqua- fully absorbed. mation of such tissues. The healthy tissues sur- Although, it is a practice to introduce the ta- rounding the wound are not affected. As a local pering end of the suppositories first and the base hemostatic, Policresulen coagulates blood pro- at last, one randomized study has found that the teins thereby inducing muscle fibers of small retention rate was higher and spontaneous expul- vessels to contract and thus any hemorrhage in sion rate was lower when the suppositories was the anal canal or in the perianal area could be introduced with “base first” technique27. It was controlled. It also induces hyperemia in the postulated that reversed vermicular contractions

167 P.J. Gupta

Table I. Ingredients in suppositories, their uses and adverse effects.

Ingredients Indications Contraindications Adverse effects

Local anesthetics Anal pain due to strangulated Know sensitivity to Local irritation and anal (Lignocain, Cinchocain, hemorrhoids, anal fissure, these agents cryptitis or proctitis. Centbucridine) and post anal surgery. Steroids (Hydrocortisone, Hemorrhoids, anal fissures, Infective lesions like anal , Systemic absorption ) pruritus ani fistula abscess and cryptitis. on prolonged use Astringents [Hamamelis Anal cryptitis, pruritus ani, Known sensitivity Local reaction water, Zinc oxide, hemorrhoids Allantoin) Vasoconstrictors Hemorrhoids, hemorrhoidal Known sensitivity Headache, flushing, [Phenylephrine] thrombosis. tachycardia. Protectants and Hemorrhoids, anal fissures, Known sensitivity No specific adversity Emollients pruritus ani (Aloe vera, Zinc oxide, Calamine) Antiseptics (Boric acid, Proctitis, anal cryptitis, Known sensitivity Pruritus, local irritation Benzalkonium chloride, anal fissures and burning Framycetine sulphate) Keratolytic Anal fissures, Known sensitivity, Skin excoriations, (Aluminium Anal rhagades inflammatory bowel mucosal ulcerations. Chloride, Resorcinol) disease, pregnancy Calcium dobesilate Bleeding hemorrhoids, Known sensitivity, Agranulocytosis hemorrhoidal attack pregnancy Policresulen Hemorrhoids, anal fissures, Inflammatory bowel Local allergic reactions infective anal lesions. disease

or pressure gradient of the anal canal might have of pain in the pediatric, obstetrical and general been responsible for this finding. It was also sug- surgical practice. However, reports are available gested that a “torpedo-shaped” suppositories where these suppositories have caused complica- should be designed which would have a better tions like rectal and anal ulcerations28, rectal acceptability and efficacy. stricture29, anal stenosis, proctitis30 and peri-rec- tal cellulites31. Complications Following Use Systemic absorption of topically applied of Suppositories steroids can occur in children32. Suppositories containing non-steroidal anti-in- Calcium dobesilate is known to cause agranu- flammatory drugs are commonly used for relief locytosis33,34.

Table II. Suppositories for various ano-rectal pathologies

Pathology Ingredients in suppositories

Bleeding hemorrhoids Astringents, vasoconstrictors, protectants, Calcium dobiselate and Policresulen Hemorrhoidal thrombosis Local anesthetics, vasoconstrictors and Calcium dobiselate Anal fissure Local anesthetics, steroids, protectants, antiseptics, keratolytics and Policresulen Pruritus ani Steroids, astringents and protectants Anal cryptitis and proctitis Local anesthetics, astringents and antiseptics Anal rhagades Keratolytic, antiseptics and policresulen Post anal surgery Local anesthetics, vasoconstrictors, antiseptics and Calcium dobiselate

168 Suppositories in anal disorders: a review

Discussion may be required to educate patients on proper suppositories administration. Drug treatment for various ano-rectal condi- In conclusion, rectal administration is yet to be tions has been known since ancient times. Today, truly explored as a potential drug delivery sys- modern as well as traditional drugs are being in- tem, particularly for drugs that are either too irri- creasingly used in proctology practice. Rectal tating for the gut or are more effective when not route with local or general effects is an interest- metabolized by the liver. Suppositories offer pa- ing possibility of a treatment modality. Easy use tients an option that is less invasive and less dis- and rapid absorption are two major advantages of comforting. Suppositories could well be looked these therapeutic options4. as a convenient drug delivery system in patients Suppositories are a very feasible mode of ad- having ano-rectal symptoms. ministration for medication. The medicament is incorporated into a base, which either melts at body temperature or dissolves in the mucus se- cretions and exerts localized or systemic action. References Within the era of cost-containment and the risk of AIDS and other communicable blood borne 1) NEIGER A. Pathogenesis, clinical aspects and diseases, drug delivery through suppositories is conservative therapy of hemorrhoids. Schweiz proving an effective and viable option5. Med Wochenschr 1980; 110: 1387-1390. It is well recognized that over-the-counter 2) SIMON I. Use of the suppositories (anal cones) in therapy with suppositories is an enormously medical practice; considerations and propos- large market. Suppositories are mainly used in als. Athena 1956; 22: 253-258. proctology practice to produce a local action, 3) POLLINZI V, S ORTINI A, RIGOBELLO P, S ALA P. Clinical such as anti-inflammatory and anesthetic effect study of a new preparation in the treatment of for hemorrhoidal conditions. Preparations for he- anorectal varices. Minerva Chir 1977; 32: 27- morrhoids usually contain astringents, local anes- 34. thetics, veno-toner drugs and anti-inflammatory 4) LIEBERMAN W. The place of suppositories and components. ointments in proctologic practice (a re-ap- However, as much as suppositories are use- praisal and new data). Am J Proctol 1966; 17: 371-376. ful, there are some disadvantages of using them too. They may not be a preferred option for the 5 ZAKHARASH MP, POIDA OI. Application of prepara- patient as it is inconvenient to use them. Ab- tions relief ultra and relief advance in practice of coloproctological department. Klin Khir 2005; sorption of drugs can be erratic and unpre- 10: 9-12. dictable. Some suppositories either leak or are expelled after insertion resulting in a futile ex- 6) NEIGER A, HERMS E. The symptomatic therapy of hemorrhoids and anal eczema–a report of ex- ercise. Nevertheless, complications of serious periences from proctology practice. Schweiz nature have been reported after use of medicat- Rundsch Med Prax 1990; 79: 918-920. ed suppositories31. 7) POPRZEN V, P OPOVIC R. Spectrodensitometric de- There is, thus, a need to become more creative termination of lidocaine-chloride in antihemor- in deciding the optimal mode of delivery of rhoidal agents. Vojnosanit Pregl 1989; 46:191- drugs to the patients. This route of drug delivery 194. should be made more convenient in nursing fa- 8) SMITH RB, MOODIE J. Comparative efficacy and cilities and institutionalized care settings. It is tolerability of two ointment and suppositories important to assess if the patient can self-admin- preparations (“Uniroid” and “Proctosedyl”) in ister a suppositories or not. the treatment of second degree haemorrhoids in general practice. Curr Med Res Opin 1988; There appears to be relatively good acceptance 11: 34-40. by patients for suppositories administration, es- pecially if the value of this drug delivery system 9) NISHIKI K, KUDOH D, NISHINAGA K, IWAI K, NAKAGAWA H. Neriproct: its anti-inflammatory effect on an is explained to them, and if the ingredients of the experimentally induced model in suppositories are chosen and formulated in a the rat. Nippon Yakurigaku Zasshi 1988; 92: manner best suited to the individual patient. The 227-240. myth that suppositories are given to only those 10) SUBRAMANYAM K, PATTERSON M, GOURLEY WK. Effects who cannot swallow is required to be eliminated of preparation-H on wound healing in the rec- from the patients mind. In addition, counseling tum of man. Dig Dis Sci 1984; 29: 829-832.

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