Routes of Drug Administration

Figure: Commonly used routes of drug administration (Lippincott Illustrated Reviews: Pharmacology)

1. Enteral Routes

A. Oral

• Easy self-administration
• Safe - toxicity/overdose can be managed with activated charcoal
• Wide range of formulations available

• Variable and potentially erratic absorption (bioavailability F = 0.05 to 1)
• Low gastric pH destroys acid-labile drugs (e.g., insulin, penicillin G)
• Subject to first-pass hepatic metabolism (reduces systemic availability)
• Requires patient cooperation
• Food, GI motility, and gut microbiome can all alter absorption
• Inappropriate for unconscious or vomiting patients

• Enteric-coated preparations (e.g., omeprazole, aspirin): a chemical envelope prevents dissolution in the stomach, protecting acid-labile drugs or preventing gastric irritation
• Extended-release (ER/XR/XL/SR/CR): controlled coatings slow drug release, prolong duration of action, reduce dosing frequency, and smooth out peak/trough fluctuations. Useful for drugs with short half-lives (e.g., ER morphine reduces dosing from 6x/day to 2x/day)

B. Sublingual and Buccal

• Sublingual: drug placed under the tongue
• Buccal: drug placed between the cheek and gum

C. Rectal

2. Parenteral Routes

• Drugs poorly absorbed or inactivated in the GI tract (e.g., heparin, insulin)
• Unconscious patients
• Situations requiring rapid onset or precise dose control

Figure A: Tissue layers targeted by IV, dermal, SC, and IM injection. Figure B: Plasma concentration of midazolam after IV vs IM dosing - IV produces a much higher, faster peak (Lippincott Illustrated Reviews: Pharmacology)

A. Intravenous (IV)

• Most common parenteral route
• Bolus injection: full dose reaches systemic circulation almost immediately
• IV infusion: slower delivery, lower peak concentration, longer effect
• Permits titration of dosage; ideal in emergencies
• Required for high-molecular-weight proteins/peptides (e.g., monoclonal antibodies)
• Can deliver large volumes and irritating substances when diluted

B. Intramuscular (IM)

• Aqueous solutions are absorbed rapidly; depot preparations (in oily vehicles like polyethylene glycol) are absorbed slowly and provide sustained release as the vehicle diffuses out
• Suitable for moderate volumes
• Can accept oily vehicles and some irritating substances

C. Subcutaneous (SC)

• Slower absorption than IM (via simple diffusion); slower than IV
• Provides constant, slow, sustained effects
• Minimizes hemolysis and thrombosis risk
• Not suitable for drugs that cause tissue irritation (risk of pain and necrosis)
• Can be used for slow-release implants

D. Intradermal (ID)

• Injection into the dermis (vascular layer beneath the epidermis)
• Used for diagnostic tests and desensitization procedures

3. Other Routes

A. Inhalation

• Gases (e.g., volatile anesthetics) and aerosol preparations
• Drug deposited directly at the site of action in pulmonary disease, minimizing systemic side effects
• Nasal route targets the nasal mucosa for local effect (e.g., allergic rhinitis)

B. Transdermal

• Provides slow, sustained, continuous drug delivery
• Bypasses first-pass metabolism
• Non-invasive

C. Intrathecal / Intraventricular

D. Topical

E. Epidural

F. Rectal / Vaginal

Summary Table (Goodman & Gilman's Table 2-1)

• Lippincott Illustrated Reviews: Pharmacology, Chapter 1 (Routes of Drug Administration)
• Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 2 (Drug Absorption, Bioavailability, and Routes of Administration, Table 2-1)

Drug Absorption and Factors Influencing It

Definition

Mechanisms of Drug Absorption

Figure: The four mechanisms by which drugs cross cell membranes (Lippincott Illustrated Reviews: Pharmacology)

1. Passive Diffusion

• Requires no carrier protein, no energy
• Not saturable; shows low structural specificity
• Water-soluble drugs pass through aqueous channels/pores
• Lipid-soluble drugs dissolve directly into the lipid bilayer and cross readily

2. Facilitated Diffusion

• No energy required (no ATP)
• Can be saturated (limited number of carriers)
• Can be competitively inhibited by other substances using the same carrier

3. Active Transport

• Energy-dependent (ATP hydrolysis required)
• Saturable and competitively inhibited
• Selective for specific drug structures
• Example: absorption of levodopa via amino acid transporters in the gut

4. Endocytosis

• The cell membrane engulfs the drug, forming a vesicle that is pinched off into the cytoplasm
• Example: Vitamin B12 transported across the gut wall by endocytosis (via intrinsic factor receptors)

Factors Influencing Absorption

1. Effect of pH and Ionization (pH-Partition Hypothesis)

• Weak acid (HA): HA ⇌ H⁺ + A⁻ — the nonionized form (HA) crosses membranes; the anion (A⁻) does not
• Weak base (BH⁺): BH⁺ ⇌ B + H⁺ — the uncharged free base (B) crosses membranes; the protonated form (BH⁺) does not

Figure A: Weak acid (HA) — the nonionized form crosses the membrane. Figure B: Weak base (B) — the uncharged form crosses the membrane (Lippincott Illustrated Reviews: Pharmacology)

For weak acids: log([A⁻]/[HA]) = pH - pKa For weak bases: log([B]/[BH⁺]) = pH - pKa

• Weak acids (e.g., aspirin, pKa ~3.5) are predominantly nonionized in the acidic stomach (pH 1-2), so they are relatively well absorbed there - but the stomach's small surface area limits total absorption
• The upper intestine (pH 5-7) has a ~200 m² surface area, which overwhelmingly favors absorption of most drugs regardless of ionization
• Weak bases (e.g., morphine, pKa ~8) are more ionized in the stomach and better absorbed from the intestine

2. Blood Flow to the Absorption Site

• The intestine receives far greater blood flow than the stomach, favoring intestinal absorption
• Shock severely reduces blood flow to cutaneous tissues - SC-administered drugs will be poorly absorbed in a shocked patient
• Highly perfused tissues (liver, kidney, brain, heart) receive drug fastest after systemic absorption

3. Total Surface Area Available for Absorption

• The small intestine, with its villi and microvilli (brush border), provides a surface area of approximately 200 m² - about 1000 times that of the stomach
• This enormous surface area makes the small intestine the primary site of oral drug absorption, even for drugs that are more ionized at intestinal pH

4. Contact Time at the Absorption Surface

• Decreased transit time (e.g., severe diarrhea, hypermotility) reduces absorption by shortening contact time
• Increased transit time (e.g., constipation) may increase absorption
• Gastric emptying rate controls delivery of drug to the intestine - delayed emptying (food, high-fat meals, anticholinergic drugs) slows absorption
• Food in the stomach both dilutes the drug and slows gastric emptying, generally slowing the rate (though not always the extent) of absorption

5. P-glycoprotein (Pgp) Efflux Pump

• It pumps drugs back out of cells into the intestinal lumen, reducing net absorption
• High P-gp expression in the gut wall significantly limits bioavailability of many drugs (e.g., digoxin, cyclosporine, certain antiretrovirals)
• P-gp is associated with multidrug resistance (MDR): cancer cells that overexpress P-gp pump out chemotherapeutic agents (paclitaxel, vinca alkaloids, anthracyclines), reducing their intracellular accumulation and causing treatment failure

6. First-Pass (Presystemic) Metabolism

1. Drug enters enterocyte → may be metabolized by CYP enzymes (CYP3A4) or effluxed back into gut lumen by P-gp
2. Drug enters portal vein → transported to liver
3. Liver metabolizes or excretes drug into bile → reduced systemic availability

7. Solubility of the Drug

• Be lipid-soluble enough to cross lipid membranes
• Have some aqueous solubility to dissolve in GI fluids and reach the membrane surface

• Highly hydrophilic drugs cannot cross the lipid bilayer
• Extremely lipophilic drugs are insoluble in aqueous fluids and cannot access the absorptive surface

8. Chemical Instability of the Drug

• Acid-labile drugs (e.g., penicillin G, omeprazole) are destroyed by gastric acid - require enteric coating or parenteral administration
• Enzyme-sensitive drugs (e.g., insulin, heparin, peptide drugs) are digested by proteases in the GI tract - cannot be given orally

9. Drug Formulation

Bioavailability

• Incomplete absorption from the GI tract
• First-pass hepatic and intestinal metabolism
• P-gp efflux
• Chemical instability
• Poor formulation dissolution

Summary of Key Factors

• Lippincott Illustrated Reviews: Pharmacology, Sections III & IV (Absorption, Bioavailability)
• Harrison's Principles of Internal Medicine, Chapter 71 (Absorption and Bioavailability, First-Pass Effect)
• Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 2 (Drug Absorption and Bioavailability)