Factors Influencing Drug Distribution

• Highly perfused tissues receive a disproportionately large amount of drug after systemic absorption
• As plasma concentration of drug decreases below that of these tissues, drug leaves these tissues to be redistributed to less well-perfused sites eg. skeletal muscle and fat
• The key determinant of drug uptake by tissues is membrane permeability
• Concentration gradient for the diffusible fraction of the drug (nonionized, lipid soluble and unbound to protein) determines both rate and direction of net transfer between plasma and tissue
• Initially, concentration of drug is higher in plasma than in tissues, favouring passage from plasma into tissues
• As drug is eliminated from plasma, the concentration gradient reverses and drug begins to leave tissues to reenter the circulation
• Tissue that accumulates drug preferentially may act as a reservoir to maintain plasma concentration and prolong duration of action
• Saturating non-active tissue sites by giving repeated or large doses of a drug can result in prolonged drug effect, as drug effect now depends on metabolism rather than redistribution
• Capacity of tissues to accept a drug depends on the drug's solubility in tissue and the mass of the tissue

Lung Uptake

• First pass pulmonary uptake of some drugs (esp. lipophilic amines) can be >65%
• Not affected by ventilation/apnoea
• The lungs serve as a reservoir for release of these drugs back into systemic circulation

CNS Distribution

• Distribution of ionized water-soluble drugs to the CNS from the circulation is restricted due to limited permeability characteristics of the brain capillaries (the blood-brain barrier)
• Cerebral blood flow is the only limitation to permeation of the CNS by nonionized lipid-soluble drugs
• The blood-brain barrier is subject to change - can be overcome be admin of large doses of a drug, or disrupted by acute head injury/hypoxemia

Volume of Distribution

• Concentration (mg/mL) = Dose (mg) / Volume of distribution (mL)
• The sum of the apparent volumes of the compartments that constitute the compartmental model
• Calculated as: the dose of drug given IV divided by the resulting plasma concentration of drug before elimination begins (initial Vd, or Vd_i), or when steady state conditions are achieved (Vd_ss)
• Influenced by physicochemical characteristics of the drug:

• Lipid solubility
• Binding to plasma proteins
• Molecular size

• Poor lipid solubility and binding to plasma proteins limit passage of drugs to tissues, maintaining a high concentration in the plasma, and a small Vd
• Non-depolarising neuromuscular blocking drugs - Vd similar to ECF volume due to poor lipid-solubility

Ionization

• Most drugs are weak acids or weak bases, present in solution as ionized and nonionized molecules
• Nonionized molecules - the pharmacologically active portion:

• Usually lipid soluble, can diffuse across cell membranes of the blood-brain barrier, renal tubular epithelium, gastrointestinal epithelium and hepatocytes

• Ionized molecules:

• Poorly lipid soluble, cannot penetrate lipid cell membranes easily
• Repelled from portions of cells with similar charges
• Impaired GI absorption, limited access to drug metabolizing enzymes in hepatocytes, promotes excretion of unchanged drug as not easily reabsorbed by the renal tubular epithelium

• Degree of ionization is determined by the drug's pK and the pH of the surrounding fluid

• When pH = pK, 50% of the drug exists in both ionized and non-ionized form
• Acidic drugs are highly ionized at an alkaline pH
• Basic drugs are highly ionized at an acid pH

Ion Trapping

• Concentration differences of total drug can develop on two sides of a membrane that separates fluids with different pHs
• Due to pH difference, degree of ionization of a drug is different on each side of the membrane
• Non-ionized lipid soluble fraction of drug equilibrates across cell membranes, but total concentration of drug on each side of the membrane is different due to the fraction of the drug existing in ionized form
• Ion trapping can occur:

• When weak bases eg. opioids accumulate in the acidic stomach
• When basic drugs eg. local anaesthetics cross the placenta from mother to fetus due to fetal pH < maternal pH, and ionized fraction cannot easily return to the maternal circulation therefore is trapped in the fetus

Protein Binding

• Most drugs bind to plasma proteins to a variable degree

• Acidic drugs binding to albumin
• Basic drugs bind to alpha₁-acid glycoprotein

• Only free/unbound drug can cross cell membranes
• Vd is inversely related to protein binding - it limits passage of drug into tissues, resulting in high drug plasma concentration and a small calculated Vd
• Also affects drug clearance, as only the unbound portion is metabolized by liver and filtered by kidney, although protein binding can also facilitate removal by transporting drugs to sites of clearance
• Bonds between drug and protein are weak - ionic/hydrogen/van der Waals,
• Alterations in protein binding only important for drugs which are highly protein bound - eg. 98% -> 96% protein bound doubles plasma fraction of unbound drug, whereas 52%->50% is minimal
• Protein binding extent parallels lipid solubility, as well as the drug's concentration and number of available binding sites

• Low concentration drugs are more likely to be highly protein bound
• Higher plasma concentration of albumin causes more drug to be protein bound

• Binding of drugs to plasma albumin is often non-selective, and many drugs compete with each other for the same protein-binding sites
• Renal failure can decrease the fraction of a drug bound to protein by metabolic factors that are normally excreted competing for protein-binding sites - eg. phenytoin
• Albumin concentration can be lowered in the elderly, and in hepatic/renal disease
• Increases in plasma concentration of alpha₁-acid glycoprotein occur in response to surgery, chronic pain and acute MI