A chemical substance will impact the human physiology in specific ways, generally by binding to a particular target protein. Receptors, ion channels, enzymes, and carrier transport proteins are the main target proteins of drugs. These proteins vary in their amount throughout the body. Their situation depends on body compartment and body tissue: so that some receptors are found only in very specific locations in the body. This confers specificity of effect to the target protein when actuated by the particular chemical (drug). This confers too specificity to the drug.
A drug must find its way to its target protein to have an effect. To do this, the drug must pass a number of obstacles, jump through hoops, slide under barrier rails, and squeeze through narrow passageways. Because, the body is compartmentalized and barred up. The compartments are set apart from one another and under different conditions, conditions enforced by these barrier mechanisms.
The compartments are maintained in set conditions by homeostatic mechanisms, mechanisms that allow a certain amount of flux while maintaining the milieu within certain limits of the set condition. Beyond those limits, and the physiology breaks down. There is the intra-cellular compartment, the interstitial compartment, and the extracellular plasma fluid. These compartments are separate and distinct but communicate with one another chemically. Each compartment is maintained under separate and different conditions to that of other compartments but yet similar enough for there to be communication between compartments. The inside of the cells (intra-cellular compartment) is kept separate from the interstitial compartment by the cell membrane. The interstitial compartment is kept separate from the blood plasma by the capillary wall and its endothelium. Capillaries are intima-only vessels in series and parallel, with nothing but a single layer of squamous epithelium (including tight junctions) between them. Capillary purpose is fluid/chemical exchange.
A drug must enter the body and get to the right compartment to attach to its target protein.
Many drugs act on cell surface receptors, so they need to get into the interstitium to reach the cell basolateral membrane. They get to there from the blood plasma. Some drugs act on receptors inside the cell. They need also to cross the cell membrane. (Other drugs act on receptors only found on the apical surface of the cell membrane, such as that on the external surface of epithelia: e.g. gut lining, nephron tubule).
The most important means by which a drug crosses the cell membrane is by passive diffusion. The rate of diffusion is determined by molecule size, the concentration gradient for that molecule, its lipid solubility, its degree of ionization (drugs can have both ionized moieties and be lipid soluble), and its affinity to bind to transport (non-target) proteins. This determines the drug pharmacokinetics.
Beyond passive or simple diffusion, chemical/fluid transport is through either a facilitated diffusion, the pressure filtration of ultrafiltration, and active transport. (Osmosis can be thought of as the diffusion–or facilitated diffusion–of water).
A lipid-soluble chemical will cross the cell membrane by passive diffusion, because the cell membrane is a phospholipid bilayer. The ionic transfer of (water-soluble) substances across the cell membrane occurs only through the confines of a transmembrane glycoprotein which have been/are slotted across the cell membrane for that exact reason).
The lipid will passively move along its concentration gradient, from outside to inside the cell. This rate of diffusion is determined by molecular size, the concentration gradient, lipid solubility, degree of ionization, and protein binding of the drug that delimits its free association.
molecular size: diffusion is inversely proportional to the square root of molecule size
concentration gradient (Fick’s Law): diffusion across a membrane is proportional to the concentration gradient for that chemical across the cell membrane.
lipid solubility: non-polar substances dissolve freely in lipids and similarly lipid molecules diffuse easily through cell membranes (which are fluid at body temperature). Membrane solubility for a substance can be expressed as a coefficient between its solubility within the membrane cf. to its solubility within the (aqueous) cytosol: lipid phase / water phase.
ionization (Henderson-Hasselbalch): the degree of ionization of a drug in solution depends on the molecular structure of the drug and the pH of the solution: the pH at which 50% of the drug molecules are ionized is a constant called its “pKa”. Most drugs are weak acids or weak bases and exist in equilibrium between un-ionised and ionized forms.
protein binding: only the portion of drug that has dissociated from its transport protein is available to cross the cell membrane; the degree of protein binding affects the proportion of free drug to bound drug, and the concentration of free drug is therein dependent.
The drug has first to enter the body. a tablet is swallowed, and the drug-chemical enters across the GIT epithelium; an injection is given into a part of the body accessible by syringe with needle; the drug can be applied onto skin and absorbed through epidermis; the drug might be inhaled. Absorption is passage of drug from site of administration to body tissue substance and then into blood. Blood circulates the drug around the body. The drug leeches into the tissues from the respective vascular bed. The vascular bed supplies a flow of drug that raises its concentration in the interstitium and drug spreads toward the cells to act on surface receptors or diffuse into the cell and act there. The drug is then said to have been distributed throughout the body. That part of the drug distributed to the tissue of its target protein will now be in a position to take effect.
The cell membrane is an effective barrier to the passage of ionized molecules.
