Pharmacokinetics — Distribution
Distribution is the pharmacokinetic process by which a drug reversibly leaves the bloodstream and enters the interstitial and intracellular fluids, as well as various tissues and organs of the body. After absorption and before elimination, drugs distribute throughout the body in a dynamic, tissue-specific manner that profoundly influences their therapeutic effects, toxicity profiles, and dosing requirements. Understanding distribution is essential for predicting drug behaviour, assessing drug interactions, performing therapeutic drug monitoring, and making clinical decisions in special populations including neonates, the elderly, pregnant women, and patients with renal or hepatic disease. For the SAPC (South Africa) pharmacy examination, distribution is a core topic that frequently appears in clinical case scenarios, calculation questions, and conceptual multiple-choice questions. This chapter provides an exhaustive, clinically relevant exploration of every aspect of drug distribution relevant to South African pharmacy practice and the SAPC curriculum.
Fundamental Concepts of Drug Distribution
Definition and Physiological Significance
Distribution refers to the reversible transfer of a drug between the vascular compartment and the tissues and fluids of the body. After intravenous administration, a drug initially resides in the plasma compartment and then progressively redistributes into various body compartments driven by differences in perfusion, drug physicochemical properties, and the permeability characteristics of biological membranes. The rate of distribution to a particular tissue is determined primarily by regional blood flow (perfusion rate), while the extent of distribution is governed by the drug’s affinity for tissue components relative to plasma proteins, its lipid solubility, and the presence of active transport mechanisms.
The apparent volume of distribution (Vd) is a fundamental pharmacokinetic parameter that quantifies the theoretical volume into which a drug distributes. Unlike anatomical volumes such as plasma volume (approximately 3 litres in a 70 kg adult) or total body water (approximately 40 litres in a 70 kg adult), Vd is a proportionality constant that relates the total amount of drug in the body to its observed plasma concentration. It does not represent a real volume but rather a mathematical construct that describes the extent of drug distribution. When a drug has a small Vd (approximating plasma volume), it remains predominantly in the vascular space; when Vd is large (exceeding total body water), it indicates extensive tissue binding or sequestration outside the vascular compartment.
Determinants of Drug Distribution
Several interrelated factors determine how a drug distributes throughout the body, and understanding these determinants allows the pharmacist or clinician to predict distribution behaviour and anticipate alterations in different clinical contexts.
Cardiac output and regional blood flow are primary determinants of the rate at which drugs reach different tissues. Highly perfused organs such as the brain, heart, liver, and kidneys receive drugs rapidly, while poorly perfused tissues such as adipose tissue, bone, and skin receive drugs more slowly. The initial distribution pattern following intravenous administration reflects this perfusion differential, with drugs rapidly appearing in well-perfused organs before equilibrating with less well-perfused tissues.
Membrane permeability governs which drugs can cross specific biological barriers. Lipophilic, non-ionised drugs with low molecular weights cross most biological membranes readily by passive diffusion. In contrast, hydrophilic drugs, highly ionised drugs, and large molecules (such as proteins, peptides, and monoclonal antibodies) have limited membrane permeability and may be excluded from specific body compartments or require active transport mechanisms to enter them.
Protein binding in plasma and tissue binding are among the most important determinants of drug distribution. Drugs that are extensively bound to plasma proteins (especially albumin and α₁-acid glycoprotein) remain largely within the vascular compartment because the drug-protein complex is too large to cross capillary membranes. Only the unbound (free) fraction of a drug is pharmacologically active and available for distribution, metabolism, and elimination.
Physiological barriers such as the blood-brain barrier, placental barrier, and blood-testis barrier selectively restrict drug distribution to certain anatomical compartments. These barriers evolved to protect sensitive tissues from xenobiotics but also limit the delivery of therapeutic agents, requiring specific pharmacological strategies to overcome them when treating conditions affecting these protected sites.
Active transport mechanisms including efflux transporters (such as P-glycoprotein, breast cancer resistance protein, and multidrug resistance-associated proteins) can actively pump drugs out of cells or across barriers, limiting drug accumulation in certain tissues and contributing to phenomena such as multidrug resistance in cancer chemotherapy and limited CNS penetration of many drugs.
Apparent Volume of Distribution (Vd)
Definition and Mathematical Basis
The apparent volume of distribution (Vd) is defined by the relationship between the total amount of drug in the body (Q) and the observed plasma concentration (Cp): Vd = Q / Cp. This parameter is termed “apparent” because it may not correspond to any real anatomical space — a drug may have a Vd of 500 litres in a 70 kg person (far exceeding total body water), indicating that the drug is concentrated in tissues far more than in plasma. Conversely, a Vd of 3 litres suggests the drug remains primarily in plasma.
The Vd is calculated differently depending on the route of administration. For intravenously administered drugs, Vd = Dose / C₀, where C₀ is the extrapolated plasma concentration at time zero. For orally administered drugs, Vd must be corrected for bioavailability: Vd = (F × Dose) / C₀, where F is the bioavailability fraction. This distinction is critical for the SAPC examination because incorrect use of the bioavailability correction is a common source of error.
Clinical Interpretation of Vd Values
The magnitude of Vd provides clinically useful information about where a drug resides in the body and what interventions might affect its elimination or toxicity.
| Vd Range | Interpretation | Representative Drugs |
|---|---|---|
| < 5 L (~plasma volume) | Drug is confined to the vascular compartment; highly protein bound or hydrophilic | Heparin, warfarin, ceftriaxone |
| 5–15 L (extracellular fluid) | Drug distributes to extracellular water; does not enter cells | Aminoglycosides (gentamicin, amikacin), cephalosporins |
| 15–40 L (total body water) | Drug distributes throughout total body water | Ethanol, many barbiturates, metformin |
| > 40 L (exceeds body water) | Significant tissue binding; drug concentrated in tissues relative to plasma | Digoxin, chloroquine, quinacrine, tricyclic antidepressants |
| > 100 L | Extreme tissue sequestration; drug is predominantly in tissues | Ivermectin, pentamidine, amphotericin B |
| > 1000 L | Markedly disproportionate tissue accumulation | Some lipophilic pesticides and toxins |
Factors Affecting Vd
Age-related changes: Neonates and infants have a higher proportion of total body water (approximately 75–80% of body weight versus 60% in adults) and lower plasma protein concentrations, leading to altered Vd values for many drugs. For example, the Vd of phenytoin is lower in neonates than adults, while the Vd of aminoglycosides is relatively higher. Elderly patients have reduced total body water and increased body fat percentage (for a given weight), which decreases the Vd of water-soluble drugs and increases the Vd of lipophilic drugs.
Disease states: Nephrotic syndrome causes hypoalbuminaemia, reducing plasma protein binding and potentially increasing the free fraction of highly protein-bound drugs. However, because free drug redistributes into tissues more readily, the net effect on Vd is variable and drug-specific. Heart failure reduces cardiac output and redistributes blood flow away from peripheral tissues, potentially decreasing Vd for some drugs while increasing it for others through complex haemodynamic effects. Hypothyroidism reduces cardiac output and lean body mass, affecting Vd predictably for affected drug classes.
Obesity: Adipose tissue has a relatively low water content and blood perfusion. For lipophilic drugs, obesity can markedly increase Vd, requiring adjusted loading doses. For hydrophilic drugs, Vd correlates more closely with lean body mass, and ideal body weight or adjusted body weight should be used for dosing calculations in obese patients.
Clinical Implications of Vd
Dialysis considerations: Drugs with small Vd values (confined to plasma and extracellular fluid) are more readily removed by dialysis or haemofiltration. Drugs with large Vd values (extensively tissue-bound) are poorly removed by dialysis because most of the drug is outside the vascular space. For example, digoxin has a Vd of 3–5 L/kg, making dialysis ineffective for digoxin overdose management; instead, digoxin-specific antibody fragments (Digibind/DigiFab) are required.
Loading dose calculation: The Vd directly determines the loading dose required to achieve a target plasma concentration rapidly: Loading Dose = (Vd × Cp,target) / F. A drug with a large Vd requires a proportionally larger loading dose to achieve therapeutic concentrations. This principle is clinically important for drugs with narrow therapeutic indices such as digoxin, where accurate Vd estimation is essential for safe dosing.
Therapeutic drug monitoring interpretation: When interpreting plasma drug concentrations, the Vd must be considered. A patient with a higher-than-expected Vd may have lower plasma concentrations for a given dose due to greater tissue partitioning, which may be clinically relevant for concentration-dependent drugs.
SAPC Examination Notes on Vd
For the SAPC examination, candidates must be able to calculate Vd from given data, interpret what a particular Vd value means physiologically, and apply Vd values in loading dose calculations. A common SAPC question format provides a clinical scenario with a patient parameter (age, weight, renal function) and asks the candidate to determine the appropriate loading dose or interpret why a particular patient’s drug level is unexpectedly high or low. Remember that Vd is a proportionality constant — it does not change with dose (within the therapeutic range) but can change with disease states, age, and other physiological variables.
Example calculation: A 70 kg adult patient requires a target plasma concentration of 15 mg/L for a drug with a Vd of 0.5 L/kg and oral bioavailability of 0.8. The loading dose oral = (0.5 L/kg × 70 kg × 15 mg/L) / 0.8 = 656.25 mg, which would be rounded to 650 mg or 660 mg depending on available tablet strengths. A common error is forgetting to divide by bioavailability for orally administered drugs, which would incorrectly yield 525 mg.
Protein Binding of Drugs
Overview of Plasma Protein Binding
Most drugs circulating in plasma are reversibly bound to plasma proteins, primarily albumin, α₁-acid glycoprotein (AAG, also called orosomucoid), and to a lesser extent lipoproteins, α₂-macroglobulin, and transcortin (corticosteroid-binding globulin). The fraction of drug bound to proteins (fu, the unbound fraction) varies widely among drugs — from less than 0.01 (99% bound) for some highly protein-bound drugs to nearly 1.0 (essentially all free) for drugs that do not bind significantly to plasma proteins.
Albumin is the most abundant plasma protein (concentration approximately 40 g/L or 600 μmol/L) and binds primarily acidic and neutral drugs. Drugs bound extensively to albumin include warfarin, phenytoin, sulfonamides, NSAIDs, barbiturates, and valproic acid. Because albumin is synthesised in the liver, conditions that reduce albumin synthesis (chronic liver disease, malnutrition, burns) or increase albumin loss (nephrotic syndrome) can reduce plasma albumin concentrations and alter the protein binding of these drugs.
α₁-acid glycoprotein is an acute-phase reactant protein whose plasma concentration increases during inflammation, infection, trauma, surgery, and certain malignancies. It binds primarily basic (cationic) drugs such as propranolol, lignocaine, quinidine, imipramine, and chlorpromazine. In inflammatory states, AAG levels may increase two- to threefold, potentially reducing the free fraction of basic drugs and altering their apparent Vd and total plasma concentrations.
Clinical Significance of Protein Binding
Only the unbound (free) fraction of a drug in plasma is pharmacologically active — it is this fraction that can cross biological membranes to reach its site of action, undergo metabolism, and be eliminated by the kidneys or other organs. Protein binding therefore serves as a reservoir that temporarily sequesters drug, slowing its distribution, metabolism, and elimination. The bound fraction acts as a buffer, releasing drug to maintain the free concentration as drug is removed from the plasma.
Protein binding displacement interactions occur when two drugs compete for the same binding site on a plasma protein. The more highly bound drug can displace the less tightly bound drug, increasing the free fraction of the displaced drug. This is clinically significant primarily for drugs with:
- High protein binding (>90%)
- Low therapeutic index
- Rapid distribution or action
- Primarily hepatic metabolism
Classic displacement examples relevant to the SAPC examination:
| Displacing Drug | Displaced Drug | Clinical Consequence |
|---|---|---|
| Sulfonamides | Warfarin | Increased free warfarin → bleeding risk |
| Valproic acid | Phenytoin | Increased free phenytoin → phenytoin toxicity |
| NSAIDs | Warfarin | Increased free warfarin → bleeding risk |
| Rifampicin | Bilirubin (albumin) | Neonatal jaundice risk |
| Cimetidine | Phenytoin | Competitive displacement → increased phenytoin levels |
| Trimethoprim | Methotrexate | Increased free methotrexate → myelosuppression |
Important caveat: A common misconception is that protein binding displacement always causes immediate clinical toxicity. In reality, for many drugs, the free drug is rapidly redistributed or eliminated, and the initial increase in free concentration triggers compensatory mechanisms. However, for drugs with narrow therapeutic indices and extensive hepatic metabolism, displacement can indeed precipitate toxicity. The key principle for the SAPC examination is that protein binding displacement primarily affects the total plasma concentration (it decreases total concentration as the free fraction increases and clearance accelerates) while the free concentration may transiently change but often returns toward baseline through homeostatic mechanisms, unless the drug’s elimination is severely compromised.
Measurement of Protein Binding
The unbound fraction of a drug can be measured using various techniques including equilibrium dialysis, ultrafiltration, ultracentrifugation, and spectroscopic methods. In clinical practice, protein binding is rarely measured routinely, but knowledge of a drug’s binding characteristics is essential for interpreting total drug concentrations in therapeutic drug monitoring. For highly protein-bound drugs, the total plasma concentration may be high while the free (active) concentration remains within the therapeutic range, leading to potential misinterpretation if only total concentration is measured.
Tissue Binding
In addition to plasma protein binding, many drugs bind to specific tissue components. This tissue binding contributes substantially to the overall Vd and can create drug reservoirs that prolong drug effects. Tissue binding mechanisms include binding to intracellular proteins (e.g., digoxin binding to Na⁺/K⁺-ATPase in cardiac myocytes), sequestration in fat (lipophilic drugs), binding to melanin in the eye and skin, and binding to bone (tetracyclines, fluoroquinolones). Tissue binding is often saturable at high concentrations, which can lead to non-linear pharmacokinetics as the binding sites become saturated and apparent Vd changes with dose.
Blood-Brain Barrier
Anatomical and Physiological Basis
The blood-brain barrier (BBB) is a highly specialised interface between the cerebral circulation and the brain parenchyma that protects the central nervous system from potentially harmful substances while permitting the selective entry of essential nutrients. The BBB results from the unique properties of brain capillary endothelial cells, which are characterised by tight intercellular junctions (zonulae occludentes), a lack of fenestrations, reduced pinocytotic activity, and the presence of specific efflux transport systems. Astrocytes and pericytes provide structural and regulatory support to the BBB, maintaining its integrity and function.
The BBB is not fully developed at birth, making neonates and premature infants more susceptible to CNS drug toxicity. The developmental trajectory of the BBB varies across brain regions, with some areas (such as the area postrema, which lacks a BBB) remaining more permeable throughout life — this is clinically relevant for antiemetic drug action and for certain drug toxicities.
Drug Penetration Across the BBB
For a drug to exert central nervous system effects, it must cross the BBB. The primary determinants of BBB permeability are:
Lipophilicity: Lipophilic drugs with appropriate partition coefficients (log P values typically between 1 and 3) cross the BBB most readily. High lipophilicity can, however, lead to excessive sequestration in the lipid bilayer of endothelial cells or active efflux by transporters, creating an optimal “Goldilocks zone” of lipophilicity.
Molecular size and shape: Drugs with molecular weights below approximately 400–500 Daltons cross the BBB more readily than larger molecules. Peptides, proteins, and most monoclonal antibodies do not cross the intact BBB under normal circumstances.
Ionisation state: At physiological pH (7.4), non-ionised drug molecules cross the BBB more readily than ionised molecules. For weak bases, the fraction of non-ionised drug increases as pH decreases; for weak acids, the non-ionised fraction increases as pH increases.
Presence of specific transport mechanisms: Some drugs enter the brain via endogenous nutrient transporters. For example, levodopa is transported across the BBB by the large neutral amino acid transporter (LAT1), which is why large amino acid meals can reduce levodopa efficacy by competition for this transporter.
Efflux Transporters at the BBB
P-glycoprotein (P-gp, encoded by the ABCB1 gene) is the most clinically important efflux transporter at the BBB. It actively pumps a wide range of drugs (including many anticancer agents, immunosuppressants, cardiac glycosides, and glucocorticoids) back into the capillary lumen, limiting their CNS accumulation. Breast cancer resistance protein (BCRP, ABCG2) and multidrug resistance-associated proteins (MRPs, ABCCs) also contribute to drug efflux from the brain.
P-gp substrate examples:
- Digoxin (clinically relevant: amiodarone and verapamil inhibit P-gp, increasing digoxin levels)
- Quinidine
- HIV protease inhibitors (atazanavir, ritonavir)
- Anticancer drugs (paclitaxel, docetaxel, doxorubicin, vincristine)
- Colchicine
- Aloperidine
P-gp inhibitors (which increase CNS penetration of P-gp substrates and can precipitate toxicity): amiodarone, verapamil, diltiazem, quinidine, itraconazole, ketoconazole, erythromycin, clarithromycin, grapefruit juice.
Implications for Drug Therapy and the SAPC Examination
Understanding BBB physiology is essential for predicting CNS drug effects, avoiding CNS toxicity, and designing rational combination therapies. Key clinical principles include:
Drugs with minimal CNS penetration (poor BBB crossing): aminoglycosides (gentamicin, amikacin), heparin, insulin, most proteins and peptides, vancomycin. These drugs are used for systemic infections but do not treat CNS infections; CNS infections require drugs that cross the BBB, such as chloramphenicol, fluoroquinolones (some), third-generation cephalosporins (some, notably ceftriaxone), or metronidazole.
Drugs with significant CNS penetration (used for CNS conditions): morphine, diazepam, fluoxetine, sertraline, chlorpromazine, haloperidol, carbamazepine, phenytoin, phenobarbital, most antiretrovirals (with varying degrees of penetration), linezolid.
CNS penetration ranking for antiepileptics (relevant for CNS infections and epilepsy): among the most penetrating are phenobarbital, phenytoin, carbamazepine, and valproic acid; among the least penetrating are gabapentin, pregabalin, vigabatrin, and lacosamide (though these are still used for epilepsy, their utility in CNS infections is limited).
South African clinical context: Tuberculosis meningitis and cryptococcal meningitis are common in South Africa due to the high prevalence of HIV. Understanding which antimycobacterial and antifungal agents penetrate the BBB is critical for appropriate treatment. Rifampicin, isoniazid, pyrazinamide, and ethambutol have varying degrees of CNS penetration, with rifampicin and isoniazid being relatively more effective in the CNS. For cryptococcal meningitis, amphotericin B and flucytosine (5-FC) have good CNS penetration, while fluconazole has moderate penetration, and voriconazole/posaconazole have variable penetration depending on the formulation and specific infection being treated.
Placental Transfer of Drugs
Physiological Considerations
The placenta serves as the interface between the maternal and fetal circulations, providing nutrient exchange, gas exchange, and hormonal support for the developing fetus. Structurally, the human placenta is a haemochorial placenta, meaning that maternal blood is in direct contact with the fetal chorionic villi. The placental barrier consists of the fetal capillary endothelium, the chorionic connective tissue, the cytotrophoblast layer, and the syncytiotrophoblast layer — collectively these form a barrier that is considerably thinner than barriers in most other organs, permitting relatively efficient exchange of solutes between maternal and fetal circulations.
The extent of placental drug transfer depends on the same physicochemical properties that govern BBB penetration: molecular weight, lipophilicity, ionisation, and protein binding. Additionally, the placenta expresses drug metabolising enzymes (CYP3A7, CYP2C9, CYP2D6, sulfotransferases, and others) and efflux transporters (P-gp, BCRP) that can modify drug exposure to the fetus.
Determinants of Placental Drug Transfer
Molecular weight: Most drugs have molecular weights below 500–600 Daltons and cross the placenta readily. High molecular weight compounds (>1000 Da) such as heparin, insulin, and proteins cross the placenta in negligible quantities.
Lipophilicity: Lipophilic drugs cross the placenta more readily than hydrophilic drugs. This general principle explains why most routinely prescribed drugs achieve some degree of fetal exposure.
Protein binding: Protein-bound drug in maternal plasma is protected from transfer; only free drug is available to cross the placenta. Because fetal plasma protein concentrations are lower than maternal concentrations and fetal albumin has lower binding affinity for many drugs, the free drug fraction may be higher in the fetus, and drugs can accumulate in fetal tissues.
Placental metabolism: Some drugs are metabolised by placental enzymes before reaching the fetal circulation. CYP3A7 (the predominant fetal CYP enzyme) is relatively inefficient at drug metabolism compared to adult enzymes but can metabolise certain substrates including some benzodiazepines and antiretroviral agents.
Efflux transporters: P-gp and BCRP are expressed in the placenta (particularly on the maternal-facing syncytiotrophoblast membrane) and actively pump drugs back into maternal circulation, providing a protective efflux barrier. The role of these transporters in preventing fetal drug toxicity is significant — animal studies suggest that P-gp deficiency leads to substantially increased fetal exposure to P-gp substrate drugs.
Pregnancy Category Classification
Historically, the United States FDA assigned pregnancy categories (A, B, C, D, X) based on animal and human data regarding fetal risk. Although this classification system has been retired in favour of more narrative labelling in many jurisdictions, the categories remain relevant for the SAPC examination and for understanding historical drug safety data.
| Category | Definition | Representative Drugs |
|---|---|---|
| A | Adequate and well-controlled studies in pregnant women have failed to demonstrate risk to the fetus | Levothyroxine, folic acid |
| B | Animal studies have revealed no fetal risk, but there are no adequate studies in pregnant women; OR animal studies have shown an adverse effect that was not confirmed in women in the first trimester | Metformin, amoxicillin, metformin |
| C | Animal studies have shown adverse effects on the fetus, but there are no adequate human studies; drugs should be used only if potential benefit justifies risk | Most newer drugs, including many antiretrovirals, quinolones |
| D | Evidence of human fetal risk exists, but benefits may be acceptable despite risk (life-threatening condition, safer drug unavailable) | ACE inhibitors (2nd/3rd trimester), tetracyclines, aminoglycosides |
| X | Studies in animals or humans demonstrate fetal abnormalities; risk clearly outweighs any possible benefit | Thalidomide, methotrexate, isotretinoin, warfarin (1st trimester) |
Note on SAHPRA: The South African Health Products Regulatory Authority (SAHPRA) requires careful risk-benefit assessment for drug use in pregnancy and lactation, and has its own guidance documents. For the SAPC examination, candidates should be familiar with the general principles and should not assume that drugs can be freely used in pregnancy simply because they are commonly prescribed in adults.
Specific Drug Considerations in Pregnancy
Antibiotics in pregnancy: Penicillins, cephalosporins, and azithromycin are generally considered safe. Tetracyclines (including doxycycline) are contraindicated after the first trimester due to effects on fetal teeth and bone development. Fluoroquinolones are generally avoided due to potential effects on fetal cartilage. Trimethoprim (folate antagonist) is avoided in the first trimester if possible. Aminoglycosides carry a risk of fetal ototoxicity (8th cranial nerve damage) and nephrotoxicity.
Antiretrovirals in pregnancy: Prevention of mother-to-child transmission (PMTCT) of HIV is a critical public health priority in South Africa. South African guidelines recommend that all pregnant women with HIV receive antiretroviral therapy (ART) regardless of CD4 count or clinical stage. Common ART regimens include tenofovir, emtricitabine (or lamivudine), and efavirenz (or lopinavir/ritonavir). Understanding the safety profiles and placental transfer characteristics of these agents is essential. Efavirenz has historically been associated with neural tube defects in animal studies (category D in the old system), though human data have been more reassuring; SAHPRA guidance should be consulted for current recommendations.
Anticoagulants in pregnancy: Warfarin is teratogenic (warfarin embryopathy: nasal hypoplasia, stippled epiphyses) and is contraindicated in the first trimester and near term. Low molecular weight heparins (LMWH, such as enoxaparin) and unfractionated heparin do not cross the placenta and are the anticoagulants of choice in pregnancy. South African obstetric haematology guidelines follow international consensus on this point.
Antiepileptic drugs in pregnancy: Many antiepileptic drugs are teratogenic or associated with fetal malformations. Valproic acid is particularly associated with neural tube defects (1–2% risk) and cognitive impairment in exposed children. Carbamazepine is associated with spina bifida (0.5% risk). Lamotrigine and levetiracetam are generally considered to have better fetal safety profiles. South African neurologists and obstetricians managing pregnant patients with epilepsy follow guidelines that advocate for the lowest-effective-dose monotherapy approach where possible, with high-dose folic acid supplementation.
Breast Milk Drug Transfer
Physiology of Lactation and Drug Excretion
Breast milk production involves the secretion of milk from alveolar epithelial cells into the lumen of mammary alveoli, from which it is expelled through the ductal system. Drugs can enter breast milk by passive diffusion across the alveolar epithelial cell membranes, by carrier-mediated transport, or by transport through paracellular pathways. The composition of breast milk (high lipid content in hindmilk, presence of milk-specific proteins and enzymes) influences drug partitioning into milk.
The extent of drug excretion in breast milk depends on the same physicochemical properties that govern other distribution processes, but with specific emphasis on:
pKa: Weakly basic drugs (such as morphine, amphetamine, and caffeine) become ionised in the acidic breast milk environment (milk pH approximately 7.0–7.2, slightly lower than plasma pH 7.4) and may become trapped (ion trapping) in milk. Weakly acidic drugs tend to have lower milk-to-plasma (M/P) ratios.
Lipophilicity: Lipophilic drugs partition into the lipid phase of milk more readily than hydrophilic drugs, increasing their concentration in milk.
Molecular weight: Low molecular weight drugs (<200 Da) transfer more readily than larger molecules.
Protein binding: Drugs with low plasma protein binding have higher free fractions available for transfer into milk.
Estimated Infant Exposure
The infant dose via breast milk is estimated as: Infant Dose = (C_milk × V_milk_intake) / (maternal_dose × fu). The relative infant dose (RID), calculated as (infant dose / maternal dose) × 100%, is used to assess safety. An RID of <10% is generally considered compatible with breastfeeding, though this threshold is not absolute and depends on the specific drug and infant factors.
| Drug | Milk-to-Plasma Ratio | Relative Infant Dose (RID) | Breastfeeding Recommendation |
|---|---|---|---|
| Morphine | 2.5–3.0 | 3–4% | Generally safe; monitor infant for sedation |
| Methadone | 2.5–3.0 | 2–5% | Compatible in low doses; high doses may cause infant withdrawal |
| Diazepam | 2.0–3.0 | 3–10% | Caution; active metabolite accumulates; avoid chronic use |
| Carbamazepine | 0.5–0.6 | 2–5% | Generally safe; monitor infant for drowsiness |
| Valproic acid | 0.4–0.5 | 1–4% | Generally safe; rare hepatotoxicity risk |
| Fluoxetine | 0.5–1.0 | 2–6% | Caution; long half-life of active metabolite |
| Sertraline | 0.5–1.0 | 1–3% | Preferred SSRI in breastfeeding; monitor infant |
| Atenolol | 1.0–3.0 | 5–15% | Caution; β-blocker effects in infant possible |
| Metoprolol | 1.0–2.0 | 1–3% | Generally safe |
| Warfarin | 0.01–0.1 | <1% | Safe; highly protein bound; minimal milk transfer |
| Citalopram | 0.5–1.5 | 3–6% | Monitor infant for irritability, poor feeding |
| Lamotrigine | 0.6–1.0 | 9–18% | Higher transfer; monitor infant for sedation, rash |
South African Context: HIV and Breastfeeding
South Africa has significant public health policies regarding breastfeeding among HIV-positive mothers. Current SAHPRA and National Department of Health guidelines recommend that HIV-positive mothers who are on effective antiretroviral therapy (ART) should breastfeed, as the benefits of breastfeeding (nutrition, immunological protection, bonding) outweigh the risks of HIV transmission when maternal viral load is suppressed. This has implications for drug excretion in breast milk, as many ARTs are excreted in breast milk to varying degrees.
Key ART considerations for breastfeeding:
- Tenofovir, emtricitabine, and lamivudine have relatively low concentrations in breast milk and are considered compatible with breastfeeding.
- Efavirenz has moderate breast milk concentrations; however, it remains a component of first-line regimens.
- Protease inhibitors (lopinavir/ritonavir) have limited data but are generally present in breast milk at low concentrations.
- Dolutegravir is increasingly used in South African first-line regimens and has favourable characteristics for breastfeeding.
Understanding the safety profile of maternal medications during lactation is a critical competency for pharmacists advising breastfeeding mothers in South Africa, particularly given the high prevalence of HIV and the national commitment to breastfeeding promotion even among HIV-positive mothers on ART.
Drugs Contraindicated or Cautious During Breastfeeding
Absolute contraindications (avoid breastfeeding): antineoplastic agents (cyclophosphamide, methotrexate), immunosuppressants (mycophenolate, sirolimus), radiopharmaceuticals, illicit drugs of abuse (cocaine, heroin, methamphetamine).
Drugs requiring caution or temporary cessation: iodinated contrast media (temporary cessation recommended), amiodarone (high iodine content, long half-life), lithium (monitor infant levels), benzodiazepines (avoid chronic use; use short-acting agents if necessary).
Redistribution
Mechanism of Redistribution
Redistribution is the process by which a drug initially concentrated in highly perfused tissues (such as the brain, heart, liver, and kidneys) subsequently redistributes to less well-perfused tissues (particularly adipose tissue and muscle) as plasma concentrations decline and equilibrium is approached. This process is particularly relevant for highly lipophilic drugs that have rapid distributive phases and slow elimination.
The classic example of redistribution determining drug effect is thiopentone (thiopental), a barbiturate anaesthetic agent. After intravenous administration, thiopentone rapidly enters the brain (highly perfused, lipid-rich tissue) producing anaesthesia within one arm-brain circulation time. However, because thiopentone is highly lipophilic, it subsequently redistributes from the brain back to plasma and then into muscle and fat. As the brain concentration falls due to redistribution, the patient awakens from anaesthesia — even though thiopentone remains in the body and is still being metabolised. This explains why a single dose of thiopentone produces only brief anaesthesia despite a relatively long elimination half-life.
Factors Influencing Redistribution
Lipophilicity: More lipophilic drugs undergo more extensive redistribution to adipose tissue. The fat-to-plasma partition coefficient of a drug determines how readily it accumulates in adipose tissue and how slowly it subsequently redistributes out of fat.
Body composition: Obesity increases the capacity of adipose tissue to sequester lipophilic drugs, potentially increasing Vd and prolonging the terminal elimination half-life. Conversely, cachexia (wasting) reduces adipose tissue stores and may alter the redistribution kinetics of lipophilic drugs.
Cardiac output: Reduced cardiac output (as in heart failure or shock) slows the rate of redistribution to well-perfused tissues and can prolong drug effects. Conversely, increased cardiac output (as in pregnancy, hyperthyroidism, or fever) may accelerate distribution to tissues.
Tissue blood flow: Regional blood flow differences determine the rate at which different tissues receive drug. In patients with peripheral vascular disease or shock, blood flow to muscle and fat is reduced, potentially altering redistribution patterns.
Clinical Implications of Redistribution
Anaesthesia and sedation: Understanding redistribution is essential for dosing intravenous anaesthetics and sedatives. Repeated or continuous administration of thiopentone or propofol can saturate adipose tissue stores, preventing further redistribution and leading to accumulation and prolonged sedation. This is why thiopentone is suitable only for induction of anaesthesia rather than maintenance, while propofol (also highly lipophilic) requires careful titration in longer procedures.
Single versus repeated dosing: A drug that has a long terminal half-life due to slow elimination may still be suitable for once-daily dosing if redistribution out of tissues maintains therapeutic plasma concentrations. Conversely, a drug with a short elimination half-life may require multiple doses if its distribution half-life is brief and redistribution does not sustain plasma concentrations.
Special populations: Elderly patients have reduced muscle mass and increased body fat percentage, which can alter redistribution of lipophilic drugs. Neonates have a higher proportion of total body water and less adipose tissue, affecting redistribution of water-soluble and lipophilic drugs differently. These differences contribute to altered drug responses in these populations.
Drugs with Significant Redistribution
| Drug | Key Redistribution Characteristics |
|---|---|
| Thiopental (thiopentone) | Classic example; redistribution terminates CNS effect after single dose |
| Propofol | Redistribution contributes to short duration after bolus; accumulation with infusion |
| Diazepam | Highly lipophilic; redistribution contributes to termination of acute effects; active metabolites complicate picture |
| Fentanyl | Highly lipophilic; redistribution to muscle and fat; terminal elimination slower than redistribution |
| Bupivacaine | Local anaesthetic; redistribution from nerve tissue terminates nerve block |
| Alfentanil | Less lipophilic than fentanyl; faster redistribution; shorter duration |
Tissue Penetration and Reservoirs
General Principles of Tissue Penetration
Tissue penetration refers to the ability of a drug to achieve adequate concentrations within specific tissues or anatomical compartments relative to plasma. The relationship between tissue and plasma concentrations varies widely among drugs and is influenced by tissue blood flow, tissue composition, membrane permeability, protein binding, active transport, and intracellular binding.
At steady state, the ratio of tissue to plasma concentration (Kp or tissue-to-plasma partition coefficient) is constant for each drug and can be greater than, less than, or equal to 1. A drug with a tissue-to-plasma ratio of 10 is present at ten times the plasma concentration in that tissue. This has profound implications for therapeutic efficacy — a drug that achieves excellent plasma concentrations may still be ineffective against an intracellular pathogen if it does not penetrate the relevant cells.
Tissue-Specific Penetration Challenges
Intracellular infections: Many pathogens reside within cells (Mycobacterium tuberculosis in macrophages, HIV in CD4+ T-lymphocytes, Plasmodium in erythrocytes). Drugs must penetrate these cells to exert their antimicrobial effects. For example, pyrazinamide penetrates mycobacterial cells well (contributing to its efficacy against intracellular TB), while rifampicin penetrates reasonably well but may be limited by efflux mechanisms. Understanding which drugs achieve adequate intracellular concentrations is essential for designing effective antimicrobial regimens.
CNS infections: As discussed in the BBB section, achieving adequate CNS concentrations requires drugs with specific physicochemical properties. The CSF-to-plasma ratio varies widely: chloramphenicol achieves CSF concentrations of approximately 50–90% of plasma concentrations (good for meningitis), while aminoglycosides achieve less than 5% (poor for meningitis).
Prostatic penetration: The prostate has a lipid-rich stromal matrix and an epithelial barrier that limits drug penetration. Basic drugs (which are ionised in the acidic prostatic fluid) accumulate in the prostate to varying degrees. Trimethoprim has relatively good prostatic penetration, which historically supported its use in bacterial prostatitis, though fluoroquinolones are now preferred for this indication.
Intraocular penetration: The eye is divided into anterior and posterior compartments with different barriers. Topically applied drugs must penetrate the cornea to reach the anterior chamber. Systemic drugs face the blood-aqueous barrier and blood-retinal barrier. Intravitreal injection is used for drugs that cannot penetrate systemically, such as antivirals for CMV retinitis or anti-VEGF agents for age-related macular degeneration.
Drug Reservoirs
Some tissues act as drug reservoirs, storing drug and slowly releasing it back into the plasma, thereby prolonging the terminal elimination phase. These reservoirs can have clinically important implications for dosing intervals, toxicity, and drug interactions.
Adipose tissue as a reservoir: Lipophilic drugs (such as many benzodiazepines, barbiturates, and some antipsychotics) accumulate in adipose tissue. While this storage is generally inert, it can prolong the terminal half-life and contribute to delayed toxicity, particularly in obese patients or after rapid weight loss (which can mobilise stored drug back into plasma). Diazepam and its active metabolites have a prolonged terminal half-life partly due to adipose tissue storage.
Bone as a reservoir: Tetracyclines (especially doxycycline and minocycline) chelate calcium and become incorporated into bone and teeth. This property underlies both their therapeutic use in osteomyelitis (where they may be beneficial) and their contraindication in children (where they cause permanent tooth discoloration and affect bone development). Fluoroquinolones also bind to bone and cartilage, which is the basis for their contraindication in children and pregnant women.
Myocardial tissue as a reservoir: Digoxin binds specifically to Na⁺/K⁺-ATPase in cardiac myocytes. This tissue binding creates a large Vd for digoxin and contributes to its narrow therapeutic index. The tissue reservoir also means that digoxin levels decline slowly after cessation, and digoxin-specific antibody fragments (Digibind/DigiFab) must be administered in overdose to bind circulating and tissue-bound digoxin.
Plasma protein binding as a reservoir: While not a tissue, plasma protein binding creates a circulating reservoir. As free drug is eliminated (by metabolism or excretion), bound drug dissociates from proteins to restore the free fraction equilibrium. This reservoir effect maintains free drug concentrations and slows overall elimination, extending the apparent half-life of highly protein-bound drugs.
Special Population Considerations
Neonates and Infants
Neonates and infants have distinctly different distribution characteristics compared to adults, requiring special consideration in drug dosing.
Body composition: Neonates have a higher proportion of total body water (75–80% of body weight versus 55–60% in adults) and a lower proportion of body fat. This increases the Vd of water-soluble drugs and decreases the Vd of lipophilic drugs relative to adults. For a given mg/kg dose, water-soluble drugs will have lower plasma concentrations in neonates than in adults.
Protein binding: Neonatal albumin concentrations are lower than adult values, and neonatal albumin has lower binding affinity for many drugs (particularly bilirubin-displacing drugs). This results in a higher free fraction of many drugs in neonates, increasing their susceptibility to toxicity from displaced drugs. The fetal form of albumin (pre-albumin) present in neonates binds some drugs less effectively than adult albumin.
Blood-brain barrier: The BBB is incompletely developed in neonates, particularly premature infants. This results in increased CNS penetration of drugs that would normally be excluded, potentially causing increased CNS toxicity. The developmental trajectory of the BBB continues throughout infancy.
Clinical example — phenytoin in neonates: Phenytoin is highly protein bound (approximately 90% in adults). In neonates, where albumin is lower and binding affinity is reduced, the free fraction of phenytoin is higher. Total plasma phenytoin concentrations in neonates appear lower than expected for a given dose, but free (active) concentrations may be within the therapeutic range. Therapeutic drug monitoring in neonates should preferentially measure free phenytoin concentrations when available.
Elderly Patients
Age-related physiological changes substantially alter drug distribution in the elderly.
Body composition: Progressive loss of lean muscle mass (sarcopenia) and reduction in total body water decrease the Vd of water-soluble drugs. Increased body fat percentage increases the Vd of lipophilic drugs. These changes alter the relationship between dose and plasma concentration.
Protein binding: Serum albumin concentrations decline with age, malnutrition, and chronic illness. This reduces protein binding of highly albumin-bound drugs and increases the free fraction. For drugs with narrow therapeutic indices, this can increase susceptibility to both adverse effects and loss of efficacy.
Renal and hepatic function: Declining renal and hepatic function affects drug clearance (discussed in metabolism and excretion chapters) but also indirectly affects distribution by altering the free fraction of drugs that depend on hepatic metabolism or renal excretion.
Cardiac output: Reduced cardiac output in elderly patients slows distribution to tissues, particularly poorly perfused tissues, which can delay the onset of drug effect and alter the shape of the concentration-time profile.
Patients with Renal Disease
Renal disease affects drug distribution through multiple mechanisms beyond simply reducing renal clearance.
Hypoalbuminaemia: Nephrotic syndrome causes significant urinary albumin loss, reducing plasma albumin concentrations and protein binding of acidic drugs. The free fraction of drugs like phenytoin and warfarin increases, which can initially increase Vd as free drug redistributes to tissues, but the net effect on total concentration monitoring must be carefully interpreted.
Fluid overload: Patients with nephrotic syndrome or renal failure may have expanded extracellular fluid volumes, increasing the Vd of water-soluble drugs and requiring higher loading doses to achieve target concentrations.
Uraemia: Uraemic toxins can alter protein binding by competing for binding sites on albumin and by modifying albumin structure. This increases the free fraction of many drugs, altering their distribution and clearance.
Altered tissue binding: Uraemia can alter the binding of drugs to tissues, affecting Vd in unpredictable ways for specific drugs.
Patients with Liver Disease
Reduced albumin synthesis: Chronic liver disease reduces hepatic synthesis of albumin and other plasma proteins, increasing the free fraction of protein-bound drugs. This can initially increase Vd as free drug redistributes, but also increases susceptibility to drug effects and toxicity.
Altered hepatic blood flow: Cirrhosis can reduce hepatic blood flow, affecting the clearance of high extraction ratio drugs (flow-limited drugs) and also altering the rate of distribution to the liver.
Ascites and third-spacing: Patients with decompensated cirrhosis and ascites have expanded extracellular fluid volumes, increasing the Vd of water-soluble drugs.
Portosystemic shunting: In cirrhosis with portal hypertension, shunting of blood past the liver can allow drugs that would normally undergo extensive first-pass hepatic extraction to escape metabolism, dramatically increasing their bioavailability and altering distribution.
Therapeutic Drug Monitoring and Distribution
When Distribution Matters for Monitoring
Therapeutic drug monitoring (TDM) involves measuring plasma drug concentrations to guide dosing, assess adherence, and avoid toxicity. For many drugs, plasma concentrations serve as a surrogate for tissue concentrations and, by extension, for drug effect. However, the relationship between plasma concentration and effect depends critically on the drug’s distribution.
Drugs where plasma concentration reliably reflects effect (good distribution equilibrium):
- Phenytoin (though free levels are more accurate in hypoalbuminaemia)
- Carbamazepine
- Valproic acid (though free levels preferred in certain settings)
- Gentamicin and other aminoglycosides (peak and trough concentrations)
- Vancomycin (trough concentrations)
- Digoxin (dispute exists; trough concentrations often used)
- Lithium (excellent correlation between plasma concentration and CNS effects)
- Theophylline (though the relationship between concentration and bronchodilation is relatively flat)
Drugs where plasma concentration may not reflect tissue concentration:
- Tricyclic antidepressants (tissue binding is extensive and variable)
- Some antipsychotics
- Drugs with active metabolites that contribute significantly to effect
- Drugs with delayed equilibrium between plasma and tissue compartments
Interpreting Concentrations in Altered Distribution States
When distribution is altered by disease or physiological change, plasma concentrations must be interpreted with caution.
Example: Digoxin in renal failure: Digoxin has a large Vd (3–5 L/kg) due to extensive tissue binding to Na⁺/K⁺-ATPase in cardiac myocytes and other tissues. In renal failure, the Vd of digoxin may be reduced (possibly due to competition for binding sites or changes in tissue perfusion), meaning that a given dose produces higher plasma concentrations than in a patient with normal renal function. This complicates dosing and interpretation of digoxin levels in renal failure patients.
Example: Phenytoin in hypoalbuminaemia: Total phenytoin concentrations may be misleadingly low in hypoalbuminaemic patients because reduced protein binding causes more rapid distribution and elimination of the free drug. The free phenytoin concentration may actually be within the therapeutic range despite low total concentrations. A commonly used correction formula adjusts total phenytoin concentration for low serum albumin: Corrected concentration = Measured concentration / [(0.9 × albumin) + 0.1].
Pharmacokinetic Modelling and Distribution
Two-Compartment and Multi-Compartment Models
While a one-compartment model assumes that a drug distributes instantaneously and uniformly throughout the body, a two-compartment model recognises that distribution is not instantaneous — drug enters the central compartment (plasma and highly perfused tissues) and then distributes to the peripheral compartment (less well-perfused tissues including muscle, fat, and skin) at a characteristic rate. The time course of drug concentration in plasma reflects the combined effects of distribution and elimination.
In a two-compartment model:
- The alpha phase (distribution phase) is characterised by rapid decline in plasma concentration as drug distributes from the central to the peripheral compartment.
- The beta phase (elimination phase) is characterised by slower decline as drug is eliminated from the body after distribution equilibrium has been reached.
- The terminal half-life reflects elimination and determines the time required to eliminate most of the drug after distribution equilibrium.
- The volume of distribution at steady state (Vdss) is the sum of the central compartment volume and the peripheral compartment volume and represents the theoretical volume in which the drug appears to distribute at steady state.
Clinical significance of the distribution phase: For drugs with slow distribution, the distribution half-life may be comparable to or longer than the elimination half-life, meaning that after a single dose, distribution is the primary determinant of the early concentration-time profile. After multiple dosing, accumulation in the peripheral compartment can lead to higher-than-predicted plasma concentrations and delayed toxicity (particularly with drugs that have active metabolites in the peripheral compartment).
Michaelis-Menten (Non-Linear) Distribution
Some drugs exhibit capacity-limited (saturable) distribution processes. At low concentrations, distribution may appear linear, but as doses increase and binding sites or transport mechanisms become saturated, the apparent Vd changes, leading to non-proportional relationships between dose and plasma concentration. Phenytoin is the classic example of a drug with dose-dependent pharmacokinetics, where the metabolic pathway becomes saturated at therapeutic concentrations, leading to disproportionate increases in plasma concentration with small increases in dose.
Drug Interactions Affecting Distribution
Protein Binding Displacement
As discussed in the protein binding section, drug interactions at plasma protein binding sites can alter the free fraction and apparent distribution of drugs. The clinical significance of these interactions depends on the characteristics of the displaced drug.
High-risk displaced drugs (extensive protein binding >90%, narrow therapeutic index, rapid onset of effect or toxicity): warfarin, phenytoin, digoxin, methotrexate, sulfonylureas.
Common displacing agents: NSAIDs (including aspirin), sulfonamides, valproic acid, gemfibrozil, clarithromycin, erythromycin.
Active Transport Inhibition
Drug interactions at transport proteins (particularly intestinal and hepatic transporters) can alter drug absorption, distribution, and elimination.
P-glycoprotein inhibition: Inhibitors of intestinal P-gp (such as verapamil, quinidine, amiodarone, ketoconazole, erythromycin, and grapefruit juice) can increase the absorption of P-gp substrate drugs, raising their plasma concentrations. Conversely, P-gp inducers (rifampicin, carbamazepine, phenytoin, St. John’s wort) decrease absorption and plasma concentrations of P-gp substrates.
OATP (organic anion transporting polypeptide) inhibition: Many drugs (including rifampicin, gemfibrozil, cyclosporine, clarithromycin) inhibit hepatic and/or intestinal OATP transporters, reducing the hepatic uptake and increasing the plasma concentrations of OATP substrate drugs such as statins (particularly simvastatin and rosuvastatin), valsartan, and methotrexate.
Blood-Brain Barrier Transporter Interactions
Interactions at BBB efflux transporters can significantly alter CNS drug concentrations and effects.
Example: Quinidine and ticlopidine inhibit P-gp at the BBB, potentially increasing CNS concentrations of P-gp substrate drugs. This is clinically exploited in some contexts (for example, combining quinidine with dextromethorphan to inhibit P-gp-mediated metabolism of dextromethorphan in the CNS, enhancing its antitussive effect) but can also cause toxicity.
Example: Rifampicin is a potent inducer of P-gp and CYP3A4. When co-administered with CNS-active drugs that are P-gp substrates, it can substantially reduce their CNS concentrations, potentially reducing efficacy.
South African Clinical Context and SAPC Focus Areas
Traditional Medicine Interactions
South Africa has a rich tradition of herbal and traditional medicine use. Many traditional remedies contain bioactive compounds that can affect drug distribution through induction or inhibition of transporters and metabolising enzymes. For the SAPC examination, awareness of potential interactions with traditional medicines is increasingly important in South African clinical practice.
Known interactions: St. John’s wort (Hypericum perforatum), commonly used for mild to moderate depression, is a potent inducer of CYP3A4 and P-gp, significantly reducing plasma concentrations of drugs including oral contraceptives, warfarin, digoxin, and antiretroviral agents. Garlic supplements (Allium sativum) and ginkgo biloba extracts also have documented enzyme induction and inhibition effects.
African traditional medicines: Specific compounds found in traditional medicines used in South Africa may affect drug distribution, but this remains an area of active research. The pharmacist’s role includes taking a thorough medication history that includes traditional remedies and advising patients about potential interactions.
Malaria Chemoprophylaxis and Distribution
South Africa’s endemic malaria areas (primarily KwaZulu-Natal, Limpopo, and Mpumalanga provinces) mean that pharmacists frequently counsel travellers and residents about malaria prophylaxis. Understanding the distribution characteristics of antimalarial drugs is essential.
Chloroquine accumulates in erythrocytes (where it acts against intraerythrocytic Plasmodium parasites) and has a large Vd due to extensive tissue binding. Its long terminal half-life (20–60 days) reflects this tissue sequestration. This underlies its historical use for suppressive prophylaxis and the rationale for weekly dosing regimens.
Mefloquine also has a large Vd (approximately 20 L/kg) due to extensive tissue binding, particularly in the brain (explaining its CNS side effects including vivid dreams, anxiety, and rarely psychosis). The distribution half-life of mefloquine is approximately 3 hours, and its terminal elimination half-life is approximately 20 days.
Atovaquone is highly protein bound (>99%) and has a relatively small Vd. Its distribution is primarily to plasma and erythrocytes, and its efficacy depends on achieving adequate concentrations at the site of action (mitochondrial electron transport chain in the parasite).
Tuberculosis Treatment and Distribution
TB remains a major public health challenge in South Africa. Understanding the distribution characteristics of antitubercular drugs is essential for managing TB meningitis, military TB, and complicated cases.
Rifampicin: Despite being the cornerstone of TB treatment, rifampicin has relatively limited CNS penetration (CSF concentrations approximately 10–20% of plasma concentrations in inflamed meninges, lower without inflammation). This is a significant limitation for TB meningitis treatment, where higher doses (up to 20 mg/kg) are increasingly advocated. Rifampicin’s Vd is approximately 1 L/kg, and it is extensively protein bound (~80%).
Isoniazid: Penetrates the CNS reasonably well (CSF concentrations approximately 20–30% of plasma concentrations, similar with and without inflammation). It has a small Vd (approximately 0.6 L/kg) and is minimally protein bound. Acetylation phenotype (fast versus slow acetylators) significantly affects its elimination half-life.
Pyrazinamide: Has good CNS penetration (CSF concentrations approximately 50–100% of plasma, particularly with inflamed meninges). It has a relatively small Vd (~0.7 L/kg) and is approximately 10–20% protein bound.
Ethambutol: CNS penetration is limited (CSF concentrations approximately 10–20% of plasma), which is a limitation in TB meningitis. Its Vd is approximately 3 L/kg.
HIV/AIDS and Drug Distribution
South Africa has the largest antiretroviral therapy programme in the world. Understanding the distribution characteristics of antiretrovirals is essential for managing HIV in pregnant women, neonates, and patients with opportunistic infections.
CNS penetration of antiretrovirals: Many antiretrovirals have limited CNS penetration, which is relevant for treating HIV-associated neurocognitive disorders and for preventing CNS involvement. Among NRTIs, zidovudine and emtricitabine have reasonable CNS penetration; tenofovir and lamivudine have variable penetration. Among NNRTIs, efavirenz has relatively good CNS penetration. Among PIs, lopinavir has limited penetration. Integrase inhibitors (dolutegravir, raltegravir) have moderate penetration.
Protein binding considerations: Many antiretrovirals are highly protein bound. For example, efavirenz is approximately 99.5% protein bound. In patients with hypoalbuminaemia (common in advanced HIV/AIDS), the free fraction of these drugs may increase, potentially altering their efficacy and toxicity profiles.
SAPC Examination Tips and Summary
Key Examination Points
Apparent Volume of Distribution:
- Vd = Dose / C₀ (IV); Vd = (F × Dose) / C₀ (oral)
- Vd does not represent a real anatomical space — it is a proportionality constant
- Large Vd → extensive tissue binding; small Vd → primarily plasma/extracellular fluid
- Vd determines loading dose: Loading Dose = (Vd × Cp,target) / F
- Altered Vd in disease states: hypoalbuminaemia, renal failure, liver disease, heart failure
Protein Binding:
- Only free (unbound) drug is pharmacologically active
- Protein binding displacement interactions are most clinically significant for drugs with >90% protein binding and narrow therapeutic indices
- Hypoalbuminaemia → increased free fraction of albumin-bound drugs
- α₁-acid glycoprotein increases in inflammation → affects basic drug binding
Blood-Brain Barrier:
- Lipophilicity, low molecular weight, and low ionisation at physiological pH favour CNS penetration
- P-gp and other efflux transporters limit CNS penetration of many substrates
- Aminoglycosides, heparin, and most proteins do not cross the BBB
- In South Africa, understanding BBB penetration of TB and fungal meningitis drugs is essential
Placental Transfer:
- Lipophilic, low molecular weight drugs cross most readily
- P-gp and BCRP at placenta provide protective efflux
- SAHPRA guidance and pregnancy categories inform prescribing in pregnancy
- Antiretrovirals in pregnancy: benefits of PMTCT generally outweigh risks of fetal exposure
Breast Milk:
- Milk-to-plasma ratio depends on pKa, lipophilicity, protein binding
- RID <10% is generally considered compatible with breastfeeding
- SA context: HIV-positive mothers on effective ART should breastfeed per national guidelines
Redistribution:
- Lipophilic drugs redistribute from highly perfused tissues (brain) to less perfused tissues (fat) after initial distribution
- Thiopentone is the classic example; redistribution terminates anaesthesia after single dose
- Accumulation in adipose tissue can prolong terminal elimination half-life
Tissue Reservoirs:
- Adipose tissue: lipophilic drugs (diazepam, DDT)
- Bone: tetracyclines, fluoroquinolones
- Cardiac tissue: digoxin (Na⁺/K⁺-ATPase binding)
- Plasma proteins: circulating reservoir for bound drugs
Common SAPC Trap Questions
Trap 1: Vd and elimination interpretation A common error is to assume that a drug with a large Vd is eliminated slowly. In fact, Vd and clearance are independent parameters. A drug may have a large Vd but high clearance (e.g., some anaesthetic agents), or small Vd but low clearance (e.g., warfarin). The half-life (t½ = 0.693 × Vd / CL) depends on both parameters. A drug with a large Vd and high clearance may have an intermediate half-life.
Trap 2: Protein binding and free drug in TDM When interpreting plasma drug concentrations in hypoalbuminaemic patients, remember that the total drug concentration may be within the therapeutic range while the free (active) concentration is elevated. For phenytoin, use the corrected concentration formula. For warfarin, assess INR rather than relying solely on plasma concentrations.
Trap 3: Redistribution and duration of effect Students sometimes confuse redistribution with elimination. Redistribution terminates the initial effect of a drug (such as thiopentone anaesthesia), but the drug continues to be eliminated from the body (by metabolism and excretion) over a longer period. The duration of action after a single dose is determined by redistribution, while the time to complete elimination is determined by the terminal half-life.
Trap 4: Loading dose and steady state The loading dose determines the initial plasma concentration, but it does not determine the steady-state concentration — that is determined by the maintenance dose rate and clearance. Similarly, giving a loading dose does not accelerate the achievement of steady state; it simply raises the initial concentration so that therapeutic levels are reached sooner for drugs with long half-lives.
Study Strategy for Distribution
For the SAPC examination, distribution should be studied in the context of how it affects clinical decisions. When reviewing each drug mentioned in this chapter, consider:
- What is its Vd, and what does this tell me about where the drug resides?
- How highly protein bound is it, and could disease or co-administered drugs affect this?
- Does it cross the BBB? The placenta? Is excreted in breast milk?
- Does it redistribute? What is the clinical significance?
- Does it have tissue reservoirs that prolong its effects?
- Are there any South African clinical scenarios (malaria, TB, HIV, traditional medicine use) where this drug’s distribution characteristics are particularly important?
By integrating distribution concepts with clinical knowledge, you will be well prepared for the pharmacokinetic questions in the SAPC examination and for the practical application of pharmacokinetics in your pharmacy career.