Rectal Drug Delivery

• Rectal drug delivery refers to the administration of pharmaceutical preparations, including active pharmaceutical ingredients (APIs) and excipients, via the rectum for either local or systemic effects
• The three main types of dosage forms delivered via the rectal route include solid unit dosage forms (suppositories), liquid unit dosage forms (enemas), and semi-solid dosage forms (ointments, creams)

Therapeutic Applications

• Rectal route treats rectal diseases such as perianal abscesses and hemorrhoids
• Therapeutic agents delivered via this route include steroids like hydrocortisone and prednisolone, anti-inflammatory drugs (sulfasalazine, mesalazine), anti-cancer drugs (5-fluorouracil, oxaliplatin), and NSAIDs (sulindac, celecoxib)
• Diazepam is the only FDA-approved rectal formulation in the U.S. for ambulatory treatment of early status epilepsy

Rectal Anatomy and Physiology

• The rectum, located at the end of the large intestine, terminates at the anus and serves as temporary storage for defecation
• In adults, the rectum is about 15–20 cm long with a diameter of 15–30 cm, and it contains a fluid volume of 1–3 mL with a pH of 7.2–7.4
• Rectal tissues are drained by the inferior, middle, and superior hemorrhoidal veins, but only the superior vein connects with the hepatic-portal system

The Rectal Route

• The rectum is the last, usually empty, portion of the large intestine located above the anal canal
• Drugs are easily introduced, retained, and absorbed
• The rectum has a neutral pH
• The surface area for absorption is smaller than that of the small intestine due to the absence of villi and microvilli
• The rectal route is one of the enteral routes, utilizing the digestive system (mouth, stomach, small intestine, anus)

Local vs Systemic Rectal Route

• Rectal route effectively treats local anorectal diseases like hemorrhoids and deliver drugs systemically
• The rectal route is an alternative to the oral route for antipyretic and analgesic drugs like paracetamol or diclofenac

Systemic Delivery via Rectal Route

• Useful for drugs with limited absorption in the upper gastrointestinal tract
• Useful for drugs that are unstable to proteolytic enzymes
• Useful for drugs that exhibit high hepatic first-pass effect
• Useful for drugs that cause irritation to the gastric mucosa
• Useful for drugs that require high doses and cannot be easily formulated in oral solid dosage forms

Advantages of Rectal Drug Delivery

• Rectal administration is a secondary choice after oral and intravenous routes
• It becomes the first choice in conditions such as nausea, vomiting, objectionable taste, unconsciousness during post-operative treatments, and difficulty in swallowing due to motility issues like dysphagia or inflammation

Disadvantages of Rectal Drug Delivery

• Sometimes it is neglected due to erratic absorption
• Potential dissolution problems due to the small fluid content of the rectum
• Limited absorption surface area
• Potential drug metabolism as the superior hemorrhoidal vein drains into the portal system, leading to metabolism by the hepatic portal system (first-pass effect)
• Poor patient compliance

Drug Absorption Through Rectal Route

• The Rectum Epithelium: Made of a single layer of columnar or cuboidal cells and goblet cells, which gives them comparable abilities to absorb drugs like upper gastrointestinal tract
• The surface area is around 200–400 cm², smaller than in the upper gastrointestinal tract but larger than nasal and buccal absorptive surfaces, without villi and microvilli
• The rectal region is extensively drained by the lymphatic circulation, which increases the systemic absorption of highly lipophilic drugs
• An empty rectum provides a constant, static environment compared to the upper gastrointestinal tract
• The lower rectum is drained by the lower and middle hemorrhoidal veins, bypassing the liver to allow systemic effects before liver metabolism
• Drugs delivered through the middle and lower hemorrhoidal veins are absorbed quickly and effectively
• Absorption is passive diffusion
• Insert rectal dosage forms in the lower rectum to avoid absorption by the upper hemorrhoidal vein, which supplies blood to the portal vein

Factors Affecting Rectal Drug Delivery

• Drug-associated factors include partition coefficient, solubility, degree of ionization, and particle size
• Formulation-associated factors include whether the formulation is liquid, solid, or semi-solid
• Pathology-associated factors include inflammatory bowel disease and gastro-intestinal infections
• Physiology-associated factors include rectal fluid volume and pH, presence of rectal contents and mucous, and motility