Pharmacology: Absorption Routes of Administration

Absorption Routes of Administration

• Different ways a drug can be administered:
  • Oral (sublingual or buccal, rectal)
  • Application to other epithelial surfaces (skin, vagina, nasal mucosa)
  • Inhalation
  • Injection (subcutaneous, intramuscular, intravenous, intrathecal, intravitreal)

Oral Administration

• Most small drugs are taken orally.
• Absorption begins in the small intestine.
• Non-polar drugs are absorbed directly in the mouth (e.g., buccal mucosa).
• Examples include organic nitrates, buprenorphine
• Peptides and proteins are digested in the GI tract.
• Not suitable for biopharmaceuticals.
• Drug absorption occurs via passive transfer across epithelial barriers.
• Absorption rate is determined by drug ionization and lipid solubility.
• Strong acids and bases cannot be absorbed by the GI tract because they are fully ionized.
• Intestinal drug absorption can involve carrier-mediated transport.
• Levodopa uses a carrier for phenylalanine.
• Fluorouracil uses a carrier for pyrimidines (thymine & uracil).
• Iron absorption is via specific carriers in the jejunal mucosa.
• Calcium absorption is facilitated by vitamin D-dependent carrier.

Factors Affecting GI Absorption

• 75% of orally administered drugs are absorbed within 1-3 hours.
• Factors influencing drug absorption:
  • Gut content (fed vs. fasted)
  • GI motility
  • Splanchnic blood flow
  • Physiochemical factors & drug-drug interactions
  • Genetic polymorphisms and/or drug competition for transporters
• Feeding affects gut content and splanchnic blood flow, influencing Tmax and Cmax.
• GI motility impacts absorption.
• Disorders like migraine and diabetic neuropathy can slow absorption due to gastric stasis.
• Muscarinic receptor blockers reduce motility (e.g. Metoclopramide increases motility to increase absorption)
• Diarrhoea can impair drug absorption.
• Splanchnic flow can be reduced by exercise, hypovolemia, or heart failure.
• Particle size (e.g. Digoxin plasma concentrations varied due to different formulations).
• Therapeutic drug formations aim to achieve desired characteristics like capsule/tablet formulations, release at the desired rate, some drugs for local effect.

Bioavailability and Bioequivalence

• Oral drugs must penetrate the intestinal mucosa and survive presystemic/first-pass metabolism.
• Bioavailability (F) indicates the fraction of orally administered dose reaching systemic circulation as intact drug.
• F takes into account both absorption and local metabolic degradation.
• Measurement of F involves comparing plasma drug concentration vs time curves after oral vs. intravenous administration.
• AUC (area under the curve) provides an integrated measure of drug exposure.
• F is estimated as AUC oral/AUC intravenous.
• Bioavailability is influenced by enzyme activity in the gut wall or liver, gastric pH, intestinal motility.
• Bioavailability varies among individuals under differing conditions and reflects the total drug reaching systemic circulation, not the rate of absorption.
• Rate of absorption affects peak plasma concentration and drug effect

Sublingual or Buccal Administration

• Absorption from the oral cavity is useful for rapid response and rapidly metabolized drugs.
• Examples of sublingual administration include glyceryl trinitrate and buprenorphine.
• Buccal midazolam is effective for terminating early status epilepticus in children.

Rectal Administration

• Rectal administration is mainly used for local and systemic effects.
• Examples include mesalazine suppositories/enemas for ulcerative colitis.
• Absorption can be rapid and more complete than oral.
• Rectal administration may be unreliable.
• Only a fraction of the drug enters systemic circulation.
• Useful for patients unable to take medication orally (e.g., vomiting, post-surgery, palliative surgery).

Cutaneous Administration

• Used for local skin effects (like ibuprofen) and systemic effects.
• Absorption through unbroken skin is poor for most drugs.
• Some substances (e.g., organophosphate insecticides) are well-absorbed and can cause poisoning.
• Examples include nicotine patches, oestrogen/testosterone patches, and fentanyl patches.

Nasal Sprays and Eye Drops

• Nasal sprays and eye-drops use mucosa as delivery routes.
• Peptide hormone analogues are administered as nasal sprays (e.g., antidiuretic hormone, gonadotrophin-releasing hormone, and calcitonin).
• Absorption occurs through mucosa overlying nasal-associated lymphoid tissue (similar to absorption through mucosa overlying Peyer's patches in the small intestine).

Administration by Inhalation

• Used for volatile and gaseous anaesthetics, and drugs affecting the lungs.
• Lung serves as the route of administration and elimination – rapid exchange due to large surface area and rapid blood flow.
• Drugs administered as an aerosol mist of liquid droplets or solid particles (e.g. glucocorticoids and bronchodilators).
• Objective: to achieve high local concentrations in the lung while minimizing systemic effects

Administration by Injection

• Intravenous injection: the fastest and most certain route, giving rapid, high drug concentrations, initially in the right heart and pulmonary vessels, then in systemic circulation.
• Intravenous infusion avoids uncertainties about absorption from other sites and prevents high peak plasma drug concentrations.
• Subcutaneous and intramuscular injections result in a slower effect than oral administration, and absorption depends on the injection site and local blood flow, with faster absorption occurring in areas of higher blood flow.

Why Delay Absorption?

• Delaying absorption is desirable or useful in producing local effects or prolonging systemic absorption.
• Local anaesthetic absorption can be reduced by adding adrenaline.
• The use of protamine and zinc in insulin formulations produces a long-acting insulin form.
• Longer-acting insulin analogues (glargine, detemir, and degladec) provide basal insulin levels over an extended period with a single dose, rather than several injections daily.

Intrathecal Injection

• Used in specialized cases like methotrexate for childhood leukemia (to prevent CNS relapse), local anaesthetics, opioid analgesics, baclofen (for muscle spasms), antibiotics and more.

Intravitreal Injection

• Intravitreal injections use monoclonial antibodies to target vascular endothelial growth factor (VEGF) for treatment of age-related macular degeneration and macular oedema.
• Intravitreal fusion proteins, like aflibercept, also target VEGF.