Q3 LONG ANSWER 10M ★ High-yield

Classify the routes of drug administration. Compare their advantages and disadvantages and describe the newer drug delivery systems.

Pharmacology · 2nd Professional — Para-Clinical

Classification of Routes

Category	Routes
Enteral	Oral, sublingual and buccal, rectal, and by nasogastric or gastrostomy tube
Parenteral — injection	Intravenous, intramuscular, subcutaneous, intradermal, intrathecal, intra-articular, intraperitoneal, intraosseous, intracardiac
Parenteral — other	Inhalational, transdermal, topical (skin, eye, ear, nose), vaginal, intranasal

Enteral Routes Compared

Route	Advantages	Disadvantages
Oral	Safest, most convenient, cheapest and most acceptable; self-administered; no sterility needed; a large overdose can sometimes be retrieved by lavage	Slow onset; unreliable absorption; destroyed by acid or enzymes (penicillin G, insulin); first-pass metabolism; useless in vomiting, coma, obstruction or an uncooperative patient; irritant drugs cause gastritis
Sublingual / buccal	Rapid absorption through a rich venous plexus draining into the superior vena cava, so it bypasses the portal circulation and avoids first-pass metabolism; the drug can be spat out if effects become excessive	Only for lipid-soluble, non-irritant, potent drugs in small volume — glyceryl trinitrate, nifedipine, buprenorphine, ondansetron
Rectal	Useful in vomiting, in the unconscious and in young children; partly avoids first-pass metabolism, since the lower and middle rectal veins drain systemically	Absorption is irregular; culturally unacceptable to many; local irritation. Used for diazepam in convulsions, paracetamol, and mesalazine

CLINICAL PEARL

The sublingual route works because of where the blood goes, not because the mucosa is special. Venous drainage from beneath the tongue enters the superior vena cava directly, so the drug reaches the systemic circulation without passing through the liver. That is the whole reason sublingual glyceryl trinitrate acts within a minute while the swallowed tablet is useless — over 90% of it would be destroyed on first pass.

Parenteral Routes Compared

Route	Onset and features	Cautions
Intravenous	Immediate and complete — bioavailability is 100% by definition. Allows titration to effect, large volumes, and irritant or hypertonic solutions. The route of choice in emergencies	Irreversible once given — the drug cannot be recalled; risk of sudden high concentration causing arrhythmia or collapse; thrombophlebitis, infection, air embolism, extravasation. Never for oily or insoluble preparations
Intramuscular	Onset in 10–30 minutes; absorption from the well-perfused muscle is fairly reliable; depot and oily preparations can be given	Painful; absorption is erratic in shock (muscle perfusion falls); contraindicated in bleeding disorders and on anticoagulants; nerve injury; raises creatine kinase, confusing cardiac enzyme interpretation
Subcutaneous	Slower and more sustained; self-administration is easy — insulin, heparin, adrenaline pens; implants and pellets give very prolonged release	Only small volumes of non-irritant drug; absorption unreliable in shock; lipodystrophy at repeated sites
Intrathecal	Places the drug directly in cerebrospinal fluid, bypassing the blood–brain barrier — spinal anaesthesia, methotrexate and cytarabine for CNS leukaemia, baclofen for spasticity	Requires absolute care — vincristine given intrathecally is invariably fatal, and this error has occurred repeatedly worldwide
Intraosseous	Rapid access when a vein cannot be found, especially in children and in cardiac arrest	Temporary; osteomyelitis
Intra-articular	High local concentration with minimal systemic effect — corticosteroid injection	Infection; repeated injection damages cartilage

Other Routes

Inhalational — the enormous alveolar surface gives rapid absorption for gases and volatile agents; for aerosols it delivers high airway concentrations with low systemic exposure, which is why inhaled corticosteroids can be given for years when oral ones cannot. Limited by technique and by particle size, and it can cause local irritation and bronchospasm
Transdermal — patches give sustained, controlled release with no first-pass metabolism and good adherence (fentanyl, glyceryl trinitrate, nicotine, hyoscine, oestrogen). Only for potent, lipid-soluble drugs; heat increases absorption dangerously, and local reactions occur
Topical — skin, eye, ear, nose, vagina; local effect with limited absorption, though systemic effects occur through inflamed or occluded skin, in infants, and from eye drops (timolol causing bronchospasm)
Intranasal — rapid absorption avoiding first pass; desmopressin, sumatriptan, midazolam for seizures, and naloxone for community overdose reversal

Choosing a Route, and Newer Delivery Systems

The choice depends on — the urgency; the physicochemical properties of the drug (acid stability, lipid solubility, first-pass extraction); the condition of the patient (vomiting, unconscious, shocked, uncooperative); whether a local or systemic effect is wanted; and cost and availability
Prefer the oral route wherever it will work — injections in India are over-used and expected by patients, and carry real risks of abscess, nerve injury and transmission of hepatitis B, C and HIV through unsafe practice
Sustained- and controlled-release preparations reduce dosing frequency and fluctuation, but must never be crushed, and overdose is prolonged and unpredictable
Targeted delivery — liposomes (liposomal amphotericin B and doxorubicin, which reduce toxicity by altering distribution), nanoparticles, antibody-drug conjugates (trastuzumab-emtansine), and monoclonal antibody carriers
Osmotic pumps, transdermal systems, ocular inserts and intrauterine systems deliver drug at a controlled rate over long periods, which transforms adherence
Prodrugs — designed to improve absorption, palatability or targeting: enalapril, valaciclovir, levodopa, sulphasalazine

First-pass Metabolism and Bioavailability

A drug swallowed is absorbed from the gut into the portal vein → It passes through the liver before reaching the systemic circulation → Metabolism in the gut wall and liver removes part of the dose — first-pass (presystemic) metabolism → Only the surviving fraction reaches the site of action — the bioavailability → Routes that bypass the portal circulation avoid this entirely — sublingual, transdermal, inhalational, parenteral, and partly rectal

Drug	Consequence of high first-pass extraction
Glyceryl trinitrate	Almost completely destroyed if swallowed — hence the sublingual, transdermal and intravenous routes
Lignocaine	Ineffective orally; given intravenously as an antiarrhythmic
Propranolol, morphine, verapamil	Oral doses must be much larger than parenteral ones; and bioavailability rises sharply in liver disease and portosystemic shunting, so the usual oral dose becomes an overdose
Levodopa	Over 95% decarboxylated peripherally — hence the addition of carbidopa
Insulin, penicillin G, heparin	Destroyed by gastric acid or enzymes rather than by the liver, but the result is the same — they cannot be given orally

Bioavailability is the fraction of an administered dose reaching the systemic circulation unchanged; it is 100% by definition for the intravenous route, against which all others are measured
It is reduced by poor absorption, destruction in the gut, and first-pass metabolism; and altered by food, formulation, gastric emptying and interacting drugs

Applied Aspects

Switch from intravenous to oral as soon as the patient can absorb; it reduces line infections, cost and length of stay, and is one of the easiest improvements available in any hospital
Do not give intramuscular injections to a shocked patient — absorption is unreliable and the drug may be released unpredictably once perfusion is restored
Adrenaline in anaphylaxis is intramuscular into the anterolateral thigh, not subcutaneous and not intravenous in the first instance; delay while seeking a vein has caused deaths
Label and handle intrathecal drugs separately, never at the same time as intravenous cytotoxics; the vincristine error is the reason for this rule
Unsafe injection practice remains a serious problem in India, and the cultural preference for injections should be actively addressed rather than accommodated
Check that the patient can use the delivery device — an inhaler, a pen, a patch or a suppository is useless if it cannot be managed, and this is rarely asked about
Reduce the oral dose of a high-extraction drug in liver disease; propranolol and morphine become far more available when the liver is bypassed or failing, and the standard dose then becomes toxic
Sustained-release tablets must never be crushed for a patient with swallowing difficulty or a nasogastric tube — the entire dose is released at once, and deaths have followed
Rotate injection sites for insulin and other repeated subcutaneous drugs; lipohypertrophy is painless, so patients prefer the damaged site, and absorption there is erratic
Remember that eye drops are absorbed systemically through the nasal mucosa; punctal occlusion after instillation reduces this substantially and should be taught
Depot preparations transform adherence in schizophrenia, contraception and rheumatic fever prophylaxis, and should be offered actively where regular tablet taking is the obstacle
Rectal administration is under-used in children with convulsions or vomiting, and a family taught to give rectal or buccal midazolam prevents many emergency presentations
Cost differs enormously between routes — an oral tablet may cost a fraction of the injectable equivalent, and in a system paid for out of pocket that difference decides whether treatment is completed
Absorption from any injected site depends on blood flow, which is why exercise, heat and massage accelerate it and shock delays it — relevant to insulin, adrenaline and local anaesthetic alike

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