Q2 LONG ANSWER 10M ★ High-yield

Define absorption and bioavailability. Describe the factors affecting them and add a note on first-pass metabolism.

Pharmacology · 2nd Professional — Para-Clinical

Definitions

Absorption is the movement of a drug from its site of administration into the systemic circulation.

Bioavailability is the fraction of an administered dose that reaches the systemic circulation in the unchanged form.

Bioavailability of an intravenous dose is 100% by definition, because the drug is placed directly into the circulation
Calculated as the ratio of the area under the concentration–time curve (AUC) after oral administration to that after an intravenous dose, expressed as a percentage
Bioequivalence — two formulations of the same drug are bioequivalent if their rate and extent of absorption do not differ significantly; this is the basis on which generic drugs are approved

The PH Partition Hypothesis

Most drugs are weak acids or weak bases and exist in ionised and unionised forms → Only the unionised, lipid-soluble form crosses membranes by passive diffusion → The proportion is governed by the henderson–hasselbalch relationship between the drug’s pKa and the pH of the medium → weak acids are unionised in an acid medium → absorbed from the stomach (aspirin, barbiturates) → weak bases are unionised in an alkaline medium → absorbed from the intestine (morphine, quinine, atropine) → In practice most absorption occurs in the small intestine whatever the pKa, because its surface area is enormous

CLINICAL PEARL

The pH partition rule predicts the direction, but surface area decides the outcome. A weak acid is indeed better ionised in the intestine — yet the small intestine still absorbs more of it than the stomach does, because its area is perhaps a thousandfold greater. The rule is genuinely useful for trapping phenomena — ion trapping in urine, milk and the stomach — rather than for predicting the site of absorption.

Factors Affecting Absorption

Group	Factors
Physicochemical — the drug	Lipid solubility (the most important), degree of ionisation and pKa, molecular size, particle size (finer particles dissolve faster — micronised griseofulvin), salt form, crystal form and polymorphism
Formulation	Solutions are absorbed fastest, then suspensions, capsules, tablets and coated tablets; disintegration and dissolution are the rate-limiting steps for a solid dosage form; excipients and enteric coating alter it
Gastrointestinal	PH; gastric emptying rate (faster emptying speeds absorption for most drugs); intestinal motility; splanchnic blood flow; surface area; presence of food
Presence of other substances	Calcium, iron, magnesium and aluminium chelate tetracyclines and fluoroquinolones and prevent their absorption; antacids raise gastric pH; cholestyramine binds many drugs
Disease and physiological state	Malabsorption, diarrhoea, vomiting, achlorhydria, coeliac disease, gastrectomy, cardiac failure (splanchnic congestion), migraine (gastric stasis, which is why metoclopramide is combined with analgesics)
Route	As discussed above

Food generally delays absorption; it reduces the absorption of ampicillin, tetracycline, rifampicin and levodopa, but increases that of griseofulvin, carbamazepine and lipid-soluble drugs by stimulating bile flow

First-pass Metabolism

First-pass (presystemic) metabolism is the metabolism of an orally administered drug during its passage from the gut lumen to the systemic circulation — in the gut lumen, gut wall, and above all the liver.

Drugs with high first-pass metabolism — propranolol, morphine, lignocaine, glyceryl trinitrate, verapamil, isoprenaline, testosterone, salbutamol, pethidine, chlorpromazine, imipramine, levodopa
Consequences — low and variable bioavailability, so the oral dose must be much larger than the parenteral dose (propranolol oral 40 mg against 1 mg intravenously); marked inter-individual variation
Routes that bypass it — sublingual, transdermal, rectal (partially), inhalational and all parenteral routes
It is saturable, so bioavailability rises disproportionately at higher doses; and it is reduced in liver disease and in portosystemic shunting, so ordinary doses may become toxic

Factors Modifying Bioavailability

Everything that affects absorption, plus first-pass metabolism
Formulation differences between manufacturers — historically important for digoxin, phenytoin and warfarin, where small changes in bioavailability cause clinical failure or toxicity
Enterohepatic circulation prolongs the presence of a drug and increases the effective exposure
Efflux transporters — P-glycoprotein in the gut wall pumps drug back into the lumen, reducing bioavailability; it is inhibited by verapamil, quinidine and grapefruit juice

Absorption from Different Sites

Site	Rate and features
Stomach	Small surface area; absorbs weak acids and alcohol; gastric emptying is usually the rate-limiting step for drugs absorbed lower down
Small intestine	The principal site for nearly all oral drugs — enormous surface area from villi and microvilli, rich blood supply, and a pH near neutral
Colon and rectum	Smaller area; the lower rectum drains to the systemic circulation and so partially avoids first pass
Buccal mucosa	Thin, highly vascular; rapid absorption; avoids first pass completely
Lung	Alveolar surface area of 70–100 m2 with a very thin barrier; near-instantaneous absorption of gases and fine aerosols
Skin	The stratum corneum is the barrier; absorption is greater in infants, across inflamed or abraded skin, and with occlusive dressings — hence systemic toxicity from topical steroids in children
Muscle and subcutaneous tissue	Depends on regional blood flow and on the formulation; slowed by vasoconstrictors, hastened by hyaluronidase and by massage

Bioavailability Curves

Parameter	Meaning	Determined by
Cmax	Peak plasma concentration reached	Rate and extent of absorption; must exceed the minimum effective concentration to work, and stay below the toxic level
Tmax	Time at which the peak is reached	Rate of absorption — a shorter Tmax means faster onset
AUC (area under the curve)	Total exposure to the drug	Extent of absorption — the measure of bioavailability
Minimum effective concentration	The level below which there is no effect	Determines onset and the end of action
Therapeutic window	The range between the minimum effective and the minimum toxic concentration	Narrow for digoxin, phenytoin, lithium and theophylline — hence monitoring

Two formulations may have the same AUC but different Cmax and Tmax — the same extent of absorption at a different rate. For a sustained-release product this is the intention; for an analgesic needed quickly it may make the product useless

Applied Aspects

Bioavailability matters most for drugs with a narrow therapeutic index — digoxin, phenytoin, warfarin, lithium, theophylline — where a 20% change in absorption can mean the difference between failure and toxicity
Do not switch brands casually for narrow-index drugs; where a patient is stable, the same formulation should be continued
Tetracyclines and fluoroquinolones must be separated from milk, antacids and iron by at least two hours, or they will not be absorbed at all — a common and entirely avoidable cause of treatment failure
Enteric-coated and sustained-release tablets must never be crushed, as this destroys the release mechanism and may deliver the whole dose at once
In vomiting or malabsorption, use a parenteral route rather than assuming an oral dose has been absorbed
Generic substitution is generally safe and greatly reduces cost, which matters enormously in India — provided the products are genuinely bioequivalent and quality-assured
Take levothyroxine on an empty stomach, well separated from calcium and iron, since both markedly reduce its absorption and cause apparent treatment resistance
Grapefruit juice raises the bioavailability of many drugs by inhibiting intestinal CYP3A4 and P-glycoprotein — statins, calcium channel blockers, ciclosporin
Counterfeit and substandard medicines remain a real problem in parts of the world, and are a cause of apparent treatment failure that no amount of dose adjustment will overcome

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