Route of Administration

• Route of administration (ROA) refers to how a drug gets onto or into the body
• Drugs/API (as drug products) come in many different forms designed by pharmaceutical scientists for administration or application.
• Many factors determine the choice of ROA such as: ease of administration, site and onset of action, duration of action, quantity of drug, and metabolism by the liver or excretion by the kidney.

Ease of Administration

• Prescribers assess characteristics to determine ROA.
• Difficulty swallowing may make oral administration inadvisable for older or very young patients
• Oral administration is inadvisable for patients experiencing nausea and vomiting.

Site of Action

• The choice of ROA is influenced by the desired site of action
• Local use refers to site-specific applications of drugs for the eye, ear, and local anesthesia for gums treatment.
• Systemic use refers to the absorption of a drug into the blood
• Drugs meant for systemic administration may target a specific site of action
• Trastuzumab targets HER-2 (human epidermal growth factor receptor 2) for cancer

Onset of Action

• Onset rate varies with ROA
• Oral medications for systemic use must proceed through a series of steps before they exert their therapeutic effect
• Liquid solutions or suspensions work faster than oral tablets or capsules because they are more readily available for absorption
• Tablets placed under the tongue or between the cheek and gums work quickly because the medication bypasses the stomach and liver, going directly into the bloodstream
• Drugs injected/infused directly into the bloodstream are carried immediately throughout the body
• Onset action of IV injections is seconds
• Onset action of IM and SC injections, Buccal, and Aerosols is minutes
• Onset action of injections, solutions, Suspensions, Powders, Capsules, Granules, Tablets, and Modified release is minutes to hours
• Onset action of Enteric coated Formulations is several hours
• Onset action of Depot injections and implants is days to weeks
• Onset action of Topical Preparations varies

Duration of Action

• Is how long a drug gives the desired response or is at the therapeutic level
• Controlled extended-release tablets may last for 12 to 24 hours, compared with 4 to 6 hours for the same drug in an immediate-release formulation
• Transdermal patches deliver small amounts of a drug steadily over many hours or even days
• Injections into the muscle and skin last longer than injections directly into the bloodstream

Quantity of Drug

• ROA depends on the drug amount
• A capsule filled with a lot of filler (diluent) might be preferred for a drug containing a very small amount of active ingredient.
• IV infusion is an excellent method for the systemic delivery of large quantities of material.

Metabolism by the Liver or Excretion by the Kidney

• Liver metabolism breaks down an active drug to inactive metabolites for elimination and to prevent drug accumulation
• The first-pass effect is the extent to which a drug is metabolized by the liver before reaching systemic circulation
• This influences the activity of several drugs, and such drugs are given in large oral doses or by another ROA to bypass or overcome metabolism by the liver.
• Age-related or disease-related changes in liver or kidney function can cause drug accumulation or toxicity
• Drug-drug interactions, drug accumulation, and increased toxic blood levels are risks if a patient is on multiple potent prescription drugs

Classifications of Routes of Administration

• Systemic: the drug enters blood and produces systemic effects
  • Enteral
    • Oral
    • Sublingual
    • Rectal
  • Parenteral
    • Inhalational
    • Injections
    • Transdermal
      • Intravenous
      • Intramuscular
      • Subcutaneous
      • Intra-arterial
      • Intra-articular
      • Intrathecal
      • Intradermal
• Local:
  • Skin topical
  • Intranasal
  • Ocular drops
  • Mucosal-throat, vagina, mouth, ear
  • Inhalational
  • Transdermal

Local ROA

• Administration of a drug at the site where the desired action is required
• Topical: Drug is applied to the skin or mucous membrane at various sites.
  • Skin: Ointment, cream, lotion, or powder
    • Example: clotrimazole (antifungal) for cutaneous candidiasis
  • Eye, ear, and nose: Drops, ointments, and sprays
    • Example: gentamicin eye/ear drops
  • Oral cavity: As a gel
    • Example: 2% lidocaine (for topical anesthesia)
  • Rectum
    • Enema: Drug administration into the rectum involves a liquid
      • Soap water enema acts as a lubricant, and water stimulates the rectum
    • Suppository: Drug administration into the rectum involves a solid
      • Bisacodyl causes bowel evacuation
  • Bronchi: As inhalation examples are salbutamol, ipratropium bromide, etc. for bronchial asthma and chronic obstructive pulmonary disease (COPD).

Systemic ROA

• Drugs administered by this route enter blood and produce systemic effects
• Enteral routes are oral, sublingual, and rectal
  • Oral: Dosage forms are tablet, capsule, and syrup, etc
    • Example: paracetamol tablet for fever and omeprazole capsule for peptic ulcer
  • Sublingual: Preparation is kept under the tongue
    • The drug is absorbed through the buccal mucous membrane and enters systemic circulation directly
    • Example: nitroglycerin for acute anginal attack
• Rectal: Drug can be given in solid or liquid form
  • Suppository: Can be used for local (topical) and also systemic effects
    • Example: indomethacin for rheumatoid arthritis and diazepam for status epilepticus
  • Inhalation: Volatile liquids and gases are given by inhalation for systemic effects; example: general anesthetics
  • Transdermal: Drug is administered as a patch or ointment; it delivers the drug into circulation for systemic effect
    • Used for angina, contraception, hormone replacement, and analgesia
• Systemic Parenteral Routes are routes of administration other than enteral
  • Intradermal: Drug is injected into the layers of the skin
    • Example: BCG
  • Subcutaneous (s.c./SubQ): Drug is injected under the skin in the thigh, abdomen, and arm
    • Example: insulin
  • Intramuscular (i.m.): Drugs are injected into large muscles such as the deltoid, gluteus maximus, and vastus lateralis
    • Example: diclofenac
  • Intravenous (i.v.): Drugs are injected directly into the bloodstream through a vein
    • Example: antibiotics and antifungals
  • Intrathecal: Drug is injected into the subarachnoid space
    • Example: spinal anesthetics and morphine
  • Intra-articular: Drug is injected directly into the joint space
    • Example: hydrocortisone injection for rheumatoid arthritis

Why Consider How Drugs Get Into Body?

• This is important because it affects
  • Bioavailability, or the percentage of the dose that gets into the body
  • Bioequivalence, or the similarity between two formulations of the same drug
  • Speed of drug onset, or how long it takes a drug to begin working
  • Dosing interval, or how often the drug should be given
  • Site of action of whether the drug stays local or acts systemically
  • Drugs must be absorbed unless injected directly into the bloodstream.

Drug Absorption

• Is the movement of drug molecules across biological barriers (mostly layers of cells) from the site of administration to the bloodstream.
• The rate of drug absorption is affected by:
  • Rate of release of drug from pharmaceutical preparation
  • Membrane permeability of the drug
  • Surface area in contact with the drug
  • Blood flow to the site of absorption

What Determines Rate of Release of Drug From Pharmaceutical Preparation

• Dosage Form
  • Solution: No Delay, Immediate Release
  • Capsules and Tablets: Delay (Dissolution), Followed by Rapid Release
  • Creams, Ointments, and Suppositories: No Delay, but Slow Release
• Additives (Excipients)
  • Decrease Rate of Dissolution
    • Binders
    • Coating agents
  • Increase Rate of Dissolution
    • Disintegrants
  • Variable Effects on Rate of Dissolution
    • Diluents
    • Coloring agents
    • Flavoring Agents
• Manufacturing Parameters - Tablet Compression: Hard tablets dissolve very slowly - Lyophilized Tablets: Porous and dissolve rapidly
• Delayed Release Preparations dissolve in the intestines, not in the stomach due to an enteric coating
• Sustained Release Preparations
  • Reservoir Diffusion Products: Drugs diffuse from the pill core through the membrane shell
  • Matrix Diffusion Products: Drugs diffuse through the matrix in which they are embedded

Factors the Determine Membrane Permeability of Drugs

• Lipophilicity increases membrane permeability
  • Presence of Aliphatic and Aromatic Structures
  • Absence of Polar Groups
• Ionization decreases membrane permeability
  • Weak acids in the intestines are mostly ionized at pH ranges from 6.6-7.5
  • Weak bases in the stomach are mostly ionized at pH ranges from 1-2

Factors that Determine Surface Area for Absorption

• Anatomy:
  • Low surface area: nasal cavity, buccal cavity, rectum
  • High surface area: small intestines and lungs

Oral Administration

• High Safety
• Interactions with food are at risk
• High Commercial Availability of Dosage Forms
• High cost
• Bioavailability is highly and reliably variable
• Onset of action is delayed
• Patient compliance is high

IV Administration

• Low Safety
• Interactions with food are not at risk
• Low Commercial Availability of Dosage Forms
• High Cost
• High and Reliable bioavailability
• Immediate Onset of Action
• Low Patient Compliance

SC Administration

• Oral > SC > IM > IV on Safety
• Oral > IV = IM = SC Interactions with food are at risk
• Oral > IM = SC = IV Commercial Availability of Dosage Forms
• IV > IM > SC > ORAL Cost
• IV > IM = SC > ORAL Bioavailability
• IV > IM > SC > Oral Onset of Action
• IV > IM > SC > Oral Patient Compliance

Why Consider Other Routes of Administration?

• Other than Oral and Parenteral