Bioavailability & Routes of Administration
Pharmacology · General Pharmacology · lean revision notes
Bioavailability & Routes of Administration
Bioavailability links how a drug is given to how much of it actually reaches the systemic circulation in active form. For NEET PG, this is a high-frequency, concept-driven area: first-pass metabolism, the Henderson–Hasselbalch ionisation logic, and route-specific onset/duration are repeatedly examined. Master the tables and the cut-offs and most questions become one-liners.
Definitions & core concepts
Bioavailability (F) = the fraction of an administered dose of unchanged drug that reaches the systemic circulation. By definition, intravenous (IV) bioavailability = 1 (100%) because the drug is placed directly into blood, bypassing every absorption barrier.
For any other route:
F = (AUC oral / AUC IV) × (Dose IV / Dose oral)
where AUC = area under the plasma concentration–time curve. AUC reflects extent of absorption; peak concentration (Cmax) and time to peak (Tmax) reflect rate of absorption.
High-yield: Bioavailability measures extent, not speed. Two formulations can have identical AUC (same F) but different Cmax/Tmax (different rate).
Bioequivalence = two formulations of the same drug with the same rate AND extent of absorption (Cmax, Tmax, AUC within accepted limits, conventionally 80–125% of the reference on log-transformed data). This is the basis for approving generic drugs.
Therapeutic equivalence = bioequivalent + same clinical effect and safety. Drugs with a narrow therapeutic index (digoxin, warfarin, phenytoin, lithium, levothyroxine) are most affected by small bioavailability differences, so generic substitution there demands caution.
First-pass (presystemic) metabolism
Drugs absorbed from the stomach, small intestine, and most of the large bowel drain via the portal vein to the liver before reaching systemic circulation. Metabolism during this transit — in the gut wall (CYP3A4, P-glycoprotein efflux) and liver — is the first-pass effect, and it lowers oral bioavailability.
High-yield: High first-pass metabolism is the single most common reason a drug has low oral bioavailability despite good absorption.
Classic high first-pass drugs (low oral F, often need high oral dose or alternate route): propranolol, lignocaine (lidocaine), morphine, glyceryl trinitrate (GTN), verapamil, isoprenaline, salbutamol, testosterone, oestradiol, imipramine, pethidine, chlorpromazine, levodopa, hydralazine.
| Drug | Reason it is given non-orally / high dose | Preferred route |
|---|---|---|
| Lignocaine (antiarrhythmic) | ~70% destroyed first pass | IV |
| GTN (acute angina) | Almost completely first-pass | Sublingual |
| Insulin / heparin | Peptides digested in gut | Parenteral (SC/IV) |
| Isoprenaline, salbutamol | High first pass | Inhaled / parenteral |
| Lprenorphine | High first pass | Sublingual |
Routes of administration — classification
Routes are broadly enteral (via GI tract: oral, sublingual, rectal) and parenteral (bypassing GI tract: IV, IM, SC, intrathecal, etc.), plus topical/transdermal and inhalational.
| Route | Bioavailability | First pass? | Onset | Key point |
|---|---|---|---|---|
| Intravenous (IV) | 100% (F=1) | Bypassed | Fastest (seconds) | No absorption phase; titratable; risk of toxicity/embolism |
| Sublingual | High | Avoided | Very fast (1–2 min) | Drains to SVC; GTN, buprenorphine, nifedipine |
| Inhalational | High (local + systemic) | Avoided (gas) | Very fast | Volatile anaesthetics, bronchodilators, O2 |
| Intramuscular (IM) | Generally good | Bypassed | Fast–moderate | Aqueous fast, depot slow; up to ~5 mL |
| Subcutaneous (SC) | Good | Bypassed | Moderate | Insulin, heparin, adrenaline; slower if vasoconstrictor added |
| Rectal | ~50% avoids first pass | Partially | Variable | Lower/middle rectal veins → IVC; upper rectum → portal |
| Transdermal | Variable, sustained | Avoided | Slow | Steady state; fentanyl, GTN, nicotine, hyoscine |
| Oral | Variable | Yes (full) | Slow (30–90 min) | Safest, cheapest, most convenient |
Oral (per os)
Most common, safest, most convenient, but most variable F due to first-pass metabolism, gut absorption variability, food, pH, and motility. Unsuitable in vomiting, unconsciousness, uncooperative patients, emergencies, and for drugs destroyed by gut/liver.
Sublingual / buccal
Drug dissolves under the tongue and is absorbed across the highly vascular oral mucosa into the superior vena cava, bypassing the portal system and the liver → no first pass, very rapid onset.
High-yield: Sublingual GTN works in 1–2 minutes for acute angina precisely because it skips first-pass metabolism. Drug can be spat out to terminate action if hypotension occurs (a self-controlled advantage).
Examples: GTN, isosorbide dinitrate, nifedipine (was used in hypertensive emergency — now discouraged), buprenorphine, sublingual fentanyl.
Rectal
Useful when oral route fails (vomiting, children, unconscious, post-op). About 50% of absorbed drug bypasses the liver because the lower and middle rectal veins drain to the IVC, while the upper rectal vein drains to the portal system — so first-pass metabolism is partially avoided. Absorption is often erratic and may irritate the mucosa. Examples: diazepam (paediatric seizures), paracetamol suppositories, indomethacin, prochlorperazine, bisacodyl (local).
Parenteral routes
- IV: 100% bioavailable, instantaneous, titratable; ideal for emergencies and irritant/large-volume drugs. Risks: thrombophlebitis, embolism, rapid toxicity; oily/depot or particulate suspensions must NOT be given IV.
- IM: Aqueous solutions absorbed rapidly; oily/depot forms (benzathine penicillin, depot antipsychotics, depot medroxyprogesterone) absorbed slowly for sustained action. Avoid in patients on anticoagulants (haematoma) and when measuring cardiac enzymes (can raise CK).
- SC: Slower, steadier; suited to self-administration (insulin, heparin, GLP-1 agonists, adrenaline auto-injectors). Adding adrenaline to local anaesthetic causes vasoconstriction → slows absorption → prolongs local action and reduces systemic toxicity.
- Intrathecal / epidural: Bypass the blood–brain barrier (spinal anaesthesia, intrathecal methotrexate, baclofen).
- Intra-arterial, intraperitoneal, intra-articular, intraosseous for special indications.
Transdermal
A drug reservoir/matrix patch delivers drug across intact skin for prolonged, steady (zero-order) plasma levels, avoiding first pass. Requires a lipophilic, low-molecular-weight, potent drug (small daily dose). Examples: fentanyl, GTN, nicotine, hyoscine (scopolamine) for motion sickness, clonidine, oestradiol, rivastigmine.
Inhalational
Gases and volatile liquids (general anaesthetics), aerosols, and dry powders. Huge alveolar surface area + thin membrane + rich blood supply → very rapid systemic absorption for gases. Aerosolised drugs (salbutamol, ipratropium, corticosteroids) act locally with minimal systemic exposure — a key safety advantage.
Factors affecting GI (oral) absorption
The dominant principle: only un-ionised, lipid-soluble drug crosses lipid membranes by passive diffusion.
Henderson–Hasselbalch & pH partitioning
- Weak acids (aspirin, barbiturates, penicillins) are un-ionised in acidic media → better absorbed where pH is low.
- Weak bases (morphine, atropine, quinine, amphetamine) are un-ionised in alkaline media.
For acids: pH = pKa + log ([ionised A⁻] / [un-ionised HA]) For bases: pH = pKa + log ([un-ionised B] / [ionised BH⁺])
High-yield: Although weak acids are un-ionised in the stomach, most absorption (even of weak acids) occurs in the small intestine because of its enormous surface area and long transit — surface area beats favourable pH.
High-yield: Ion trapping — alkalinising urine (sodium bicarbonate) ionises weak acids like aspirin/phenobarbitone in the renal tubule, trapping them and enhancing excretion in overdose. Acidifying urine traps weak bases.
Other GI factors
| Factor | Effect on absorption |
|---|---|
| Gastric emptying | Faster emptying → faster small-intestinal absorption (drugs mostly absorbed in jejunum). Food, anticholinergics, opioids delay emptying |
| Lipid solubility | Higher → better passive diffusion |
| Ionisation (pKa & pH) | More un-ionised fraction → better absorption |
| Particle size | Smaller → larger dissolution surface → better (e.g., micronised griseofulvin, aspirin) |
| Formulation/disintegration | Solution > suspension > capsule > tablet > coated/enteric > sustained-release for rate |
| Food | Delays/reduces most; enhances griseofulvin, lipid-soluble drugs; high-fat meal aids vitamin absorption |
| Presence of other drugs | Tetracyclines + Ca²⁺/Fe²⁺/antacids → insoluble chelates; metoclopramide speeds, opioids slow emptying |
| Gut motility & disease | Malabsorption, diarrhoea, mucosal disease alter F |
| First-pass & gut-wall CYP3A4/P-gp | Major determinant of net oral F |
Stepwise: the journey from tablet to systemic effect
Tablet → disintegration → dissolution (often rate-limiting for solids) → un-ionised drug diffuses across enterocyte membrane → gut-wall metabolism (CYP3A4) / P-gp efflux → portal vein → hepatic first-pass metabolism → systemic circulation (bioavailable fraction F) → site of action.
High-yield: For most solid oral dosage forms, dissolution is the rate-limiting step of absorption — the rationale behind micronisation, salts, and solubilising formulations.
Special pharmacokinetic points
- Disintegration vs dissolution: disintegration breaks the tablet apart; dissolution puts drug into solution — dissolution is usually the bottleneck.
- Sustained/controlled release reduces dosing frequency and smooths peaks, but F may be lower and dose-dumping is a risk if the matrix is crushed.
- Enteric coating protects acid-labile drugs (omeprazole, erythromycin) and protects the stomach (enteric aspirin), delaying onset.
- Bioavailability vs potency vs efficacy — keep distinct: F is an absorption concept, not a measure of drug effect.
Complications / clinical consequences of route choice
- IV: extravasation, air embolism, infection, anaphylaxis from rapid high levels.
- IM: sterile abscess, nerve injury (improper gluteal site → sciatic nerve), haematoma in anticoagulated patients, raised CK confounding MI diagnosis.
- Oral: erratic F, GI irritation, drug interactions, useless in vomiting/coma.
- Transdermal: local skin irritation, patch displacement, residual drug in used patches (fentanyl patch deaths).
- Sublingual: bad taste, mucosal irritation, not for large or slowly-dissolving doses.
Key differentials / comparisons to remember
| Concept | Easily confused with | Distinguish by |
|---|---|---|
| Bioavailability (extent) | Bioequivalence (rate + extent equal) | F = single formulation property; bioequivalence compares two |
| First-pass metabolism | Plasma protein binding | First pass = pre-systemic loss; binding = distribution |
| Cmax/Tmax (rate) | AUC (extent) | Rate vs amount absorbed |
| Sublingual (no first pass) | Oral (full first pass) | Venous drainage: SVC vs portal |
| Rectal (partial first pass) | Sublingual (none) | ~50% portal drainage rectally |
Recently asked / exam angle
- "Which route has 100% bioavailability?" → Intravenous.
- "Sublingual route avoids…" → First-pass hepatic metabolism (drains into SVC).
- Match the high first-pass drug (propranolol, lignocaine, GTN, morphine) — recurring assertion-reason and matching item.
- Rectal route bypasses what fraction of liver? → ~50% (lower/middle rectal veins → IVC).
- Rate-limiting step of oral absorption of a solid → dissolution.
- Aspirin overdose management → urinary alkalinisation (ion trapping); aspirin is a weak acid.
- Where are weak acids best absorbed? → small intestine (surface area), not stomach despite favourable pH.
- Bioequivalence range → 80–125% AUC of reference; relevant to generics and narrow-TI drugs (warfarin, digoxin, phenytoin, levothyroxine).
- Adding adrenaline to local anaesthetic → vasoconstriction slows absorption, prolongs action, reduces toxicity.
- Transdermal patch drugs → fentanyl, GTN, nicotine, hyoscine, clonidine, oestradiol, rivastigmine.
Mnemonic — high first-pass drugs: "PLastic Money Going Very Soon, Isn't That Lost?" → Propranolol, Lignocaine, Morphine, GTN, Verapamil, Salbutamol, Isoprenaline, Testosterone, Levodopa.
Rapid revision
- Bioavailability = fraction of unchanged drug reaching systemic circulation; IV F = 100%.
- F measures extent of absorption (AUC); Cmax/Tmax measure rate.
- Bioequivalence = same rate + extent (AUC 80–125% of reference) → basis of generics.
- First-pass metabolism (gut wall + liver) is the chief cause of low oral F.
- High first-pass drugs: propranolol, lignocaine, GTN, morphine, verapamil, salbutamol, levodopa.
- Sublingual drains to SVC → no first pass → GTN acts in 1–2 min.
- Rectal route bypasses ~50% of the liver (lower/middle rectal veins → IVC).
- Only un-ionised, lipid-soluble drug crosses membranes; pH governs ionisation (Henderson–Hasselbalch).
- Weak acids best absorbed in the small intestine (surface area > favourable gastric pH).
- Ion trapping: alkalinise urine to excrete weak acids (aspirin, phenobarbitone) in overdose.
- Dissolution is the rate-limiting step for most solid oral dosage forms.
- Transdermal needs lipophilic, low-MW, potent drugs; gives steady zero-order levels and avoids first pass.