Concept of pharmacokinetics and substance transport mechanisms
Pharmacokinetics is the study of the absorption, distribution, tissue binding, biotransformation (metabolism), and excretion of drugs in the body. Absorption is impossible without the drug crossing the cell membrane, which occurs via four mechanisms.
- Passive diffusion is transport without a carrier and without ATP consumption; available only for small, uncharged, and non-polar molecules, moving down the concentration gradient.
- Facilitated diffusion is similar to passive diffusion, but is mediated by a carrier protein, allowing the transport of larger and charged molecules.
- Active transport occurs against the concentration gradient with the consumption of ATP; it operates as uniport, symport, and antiport (substances are transported simultaneously). A classic example is the Na⁺/K⁺-ATPase.
- Pinocytosis is the engulfment of a substance by a membrane area with the formation of a vesicle; it has limited pharmacological significance.
Routes of drug administration
All routes of administration are divided into enteral (via the gastrointestinal tract) and parenteral (bypassing the gastrointestinal tract).
- Enteral: oral and rectal — ease of administration, but low bioavailability; sublingual and buccal — bypass the liver because venous drainage goes into the superior vena cava system rather than the portal vein.
- Parenteral: intravenous, intra-arterial, intramuscular, subcutaneous, inhalation, subarachnoid, intranasal, transdermal.
Intravenous and intra-arterial oily solutions must not be administered due to the risk of fat embolism. Intramuscular and subcutaneous routes are contraindicated for irritating and hypertonic solutions (e.g., magnesium sulfate). The subarachnoid route is used for spinal and epidural anesthesia with local anesthetics. The inhalation route is used for bronchial asthma and COPD.
Presystemic elimination and bioavailability
Bioavailability is the percentage of the drug that reaches the systemic circulation unchanged. Before entering the bloodstream, the drug is lost in the gastrointestinal tract and during first-pass metabolism in the liver.
- Oral and rectal — 20–50%; exception — fluoroquinolones (ciprofloxacin ~70%, others close to 100%).
- Sublingual and buccal — high, but limited by taste and absorption rate.
- Intravenous and intra-arterial — 100%.
- Intramuscular and subcutaneous — 90–95%.
- Inhalation, subarachnoid, intranasal, transdermal — generally low, as the drugs are intended for local action (e.g., fluorinated inhaled corticosteroids). Systemic exceptions: oxytocin and vasopressin intranasally, fentanyl and nicotine patches transdermally.
Distribution and volume of distribution
Distribution is uneven and depends on the drug's ability to cross tissue barriers: blood-brain barrier (BBB), blood-ocular barrier, placental barrier. Unlike the fenestrated capillaries of the periphery, brain vessels lack fenestrae, so only lipophilic substances cross the BBB via passive diffusion or active transport substrates (e.g., levodopa).
Volume of distribution (Vd) is the hypothetical fluid volume in which the drug concentration, after distribution, would equal its plasma concentration. A low Vd (~5 L) indicates the drug is predominantly in the blood; ~40 L means uniform distribution; a very high Vd (hundreds to thousands of liters) means intracellular accumulation. Clinical significance: in epidemic typhus (rickettsiae are obligate intracellular parasites), the drug of choice is doxycycline, which has a high Vd; aminoglycosides, despite being bactericidal, are ineffective due to a low Vd.
Tissue binding and biotransformation
Tissue binding (depot storage) is the accumulation of drugs in tissues (muscles, bones, fat, plasma proteins). Amiodarone is stored in adipose tissue and can cause amiodarone-induced thyrotoxicosis; discontinuing the drug does not eliminate the effect, so antithyroid drugs are added. Tetracyclines (doxycycline) accumulate in bones, which is contraindicated in children. Diclofenac binds in muscles.
Biotransformation can be specific (metabolic) or via conjugation.
- Specific: levodopa → dopamine (DOPA decarboxylase); valacyclovir → acyclovir; ethanol → acetaldehyde (alcohol dehydrogenase).
- Nonspecific: the cytochrome P450 system (hepatic microsomal enzymes), which includes numerous isoforms.
- Conjugation: attachment of glutathione, sulfate, or glucuronic acid. Paracetamol is converted via P450 into a hepatotoxic metabolite, which is detoxified by glutathione; acetylcysteine (NAC) increases glutathione levels and protects the liver.
P450 inducers (accelerate the metabolism of other drugs, weakening their effect): phenobarbital, phenytoin, griseofulvin, rifampicin. P450 inhibitors (enhance and prolong the effect of other drugs): cimetidine, levomycetin (chloramphenicol), furazolidone, metronidazole, grapefruit juice. Alcohol dehydrogenase is blocked by levomycetin, metronidazole, and cephalosporins — alcohol consumption while taking these is contraindicated.
Excretion, clearance, and elimination
Excretion is carried out primarily by the kidneys and liver; additionally by the lungs, sweat, saliva, and breast milk. Excretion in milk is clinically significant: even low drug concentrations are dangerous for a newborn with low P450 activity.
Clearance is the volume of plasma cleared of a substance per unit of time; a key clinical indicator is creatinine clearance, reflecting renal function. Elimination = excretion + biotransformation. Of practical importance is the half-life (T½) — the time required for 50% of the administered drug to be eliminated from the body; it is specified in instructions and reference books.
Dosages and steady-state concentrations
- Loading dose — for rapid achievement of therapeutic concentration.
- Maintenance dose — maintains a constant drug level in the blood (e.g., infusion of fentanyl, propofol, and a neuromuscular blocker during anesthesia, or morphine via a syringe pump).
- Minimum and maximum therapeutic doses define the efficacy range; below the minimum there is no effect, above the maximum there is a toxic effect.
- Lethal dose and LD50 — the dose causing the death of 50% of experimental animals.
Steady-state concentration (Css) is established when the rate of drug administration equals the rate of its elimination. The range between the minimum and maximum Css is called the therapeutic window (therapeutic range, therapeutic index). Exceeding Css max leads to toxicity: for example, a morphine overdose causes respiratory center depression and death.
Key points
- Pharmacokinetics includes absorption, distribution, tissue binding, biotransformation, and excretion.
- Sublingual and buccal routes bypass the liver due to drainage into the superior vena cava.
- Bioavailability is 100% for intravenous administration and typically 20–50% for oral administration.
- A high volume of distribution determines a drug's penetration into cells (doxycycline in rickettsial infections).
- Cytochrome P450 is the main system of nonspecific biotransformation; inducers and inhibitors significantly alter the effects of concomitant drugs.
- Paracetamol is hepatotoxic via a P450 metabolite; protection is provided by conjugation with glutathione, enhanced by acetylcysteine.
- Metronidazole, levomycetin, and cephalosporins block alcohol dehydrogenase — alcohol is contraindicated.
- The therapeutic window is bounded by the minimum and maximum steady-state concentrations; exceeding it leads to toxicity.