General Principles: continued

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Drugs: Some Structural Issues


Binding Forces in Drug-Receptor Interactions
  • Three major types of chemical forces/bonds:

    • Covalent--very strong

      • Frequently, a covalent bond is described as essentially "irreversible" under biological conditions. The term "irreversible" is in fact in quotes because all reactions are reversible.  However, once a covalent bond is formed, the resulting structure is typically extremely stable and although the reverse reaction occurs its occurrence may be highly improbable.

      • Examples:

        • A covalent bond is formed between the activated form of phenoxybenzamine (Dibenzyline) (α receptor antagonist) and the α-adrenergic-receptor.

          •  The covalent interaction explains the drug's long duration of action.

          •  To overcome the alpha-adrenergic receptor blockade, new alpha receptor protein must be synthesized in the inhibited receptor internalized by the cell and degraded.  This process may take 48 hours.

        • Another example of drugs that interact covalently with their targets are the DNA-alkylating chemotherapy agents.

          •  These drugs are chemically highly reactive, forming covalent bonds with DNA functional groups

          •  Such covalently-modified DNA may be incompatible with successful tumor cell division.

    • Electrostatic:-- weaker than covalent

      • Electrostatic interactions tend to be much more common than the covalent bonding in drug-receptor interactions

      • The interaction strength is variable:

        •  Strong electrostatic interactions occur between between permanently charged ionic molecules

        •  Weaker interactions all are due to hydrogen bonding

        •  Still weaker interactions are called induced-dipole interactions, e.g. van der Waals forces

    • Hydrophobic interactions referred to interactions between molecules in which the interactions are less driven by molecule to molecule attraction and more by the tendency of molecules to wish to avoid the aqueous (water) environments:

      • Hydrophobic interactions are generally weak, but important.

      • Hydrophobic interactions are probably significant in driving interactions:

        •  between lipophilic drugs and the lipid component of biological membranes

        •  between drugs and relatively nonpolar (not charged) receptor regions

Katzung, B. G. Basic Principles: Introduction in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p.1-4.


Henderson-Hasselbalch equation


log (protonated)/(unprotonated) = pKa - pH

  1. the lower the pH relative to the pKa: greater fraction of protonated drug (protonated drug may be charged or uncharged)

  2. weak acid at acid pH: more lipid-soluble, becauses it is uncharged--the uncharged form more readily passes through biological membranes.

    • note that a weak acid at acid pH will pick up a proton a become uncharged.

    • RCOO- + H+  RCOOH

  3. weak base at alkaline pH: more lipid-soluble, because it is uncharged--the uncharged form more readily passes through biological membranes.

    • note that a weak base at more alkaline pH will lose a proton, becoming uncharged

    • RNH3+  RNH2 + H+

  • Lipid diffusion depends on adequate lipid solubility

    • Drug ionization reduces a drug's ability to cross a lipid bilayer.


Many drugs are weak acids or weak bases

  • weak acid: a neutral molecule that dissociates into an anion (negatively charged) and a proton (a hydrogen ion) Example:

    • C8H7O2COOH C8H7O2COO- + H+

    • neutral aspirin (C8H7O2COOH) in equilibrium with aspirin anion (C8H7O2COO- ) and a proton (H+ )

    • weak acid: protonated form -- neutral, more lipid-soluble

  • weak base:a neutral molecule that can form a cation (positively charged) by combining with a proton. Example:

    • C12H11CIN3NH3+ C12H11CIN3NH2 + H+

    • pyrimethamine cation (C12H11CIN3NH3+) in equilibrium with neutral pyrimethamine (C12H11CIN3NH2) and a proton (H+ )

    • weak base: protonated form -- charged, less lipid-soluble


Models of Drug Transfer

Above figure courtesy of Professor Steve Wright and the University of Arizona (c), used with permission

Aqueous diffusion 

  • Occurs within large aqueous components (e.g.,interstitial space, cytosol)

  • Occurs across epithelial membrane tight junctions

"Structure of tight junctions. a | Freeze-fracture replica electron microscopic image of intestinal epithelial cells. Tight junctions appear as a set of continuous, anastomosing intramembranous particle strands or fibrils (arrowheads) on the P face with complementary vacant grooves on the E face (arrows). (Mv, microvilli; Ap, apical membrane; Bl, basolateral membrane.) Scale bar, 200 nm. b | Ultrathin sectional view of tight junctions. At kissing points of tight junctions (arrowheads), the intercellular space is obliterated. Scale bar, 50 nm. c | Schematic of three-dimensional structure of tight junctions. Each tight-junction strand within a plasma membrane associates laterally with another tight-junction strand in the apposed membrane of an adjacent cell to form a paired tight-junction strand, obliterating the intercellular space (kissing point)."--from Nature Reviews Molecular Cell Biology 2; 285-293 (2001) MULTIFUNCTIONAL STRANDS IN TIGHT JUNCTIONS

  • Occurs across endothelial blood vessel lining

    • through aqueous pores: allows diffusion of large molecules with molecular weights up to 20,000 -- 30,000.

  • Driving force: drug concentration gradient (described by Fick's Law )

Fick's Law


Definition: Fick's Law describes passive movement molecules down its concentration gradient.


Flux (molecules per unit time) = (C1 - C2) · (Area ·Permeability coefficient) / Thickness

  •  where C1 is the higher concentration and C2 is the lower concentration

  •  area = area across which diffusion occurs

  •  permeability coefficient: drug mobility in the diffusion path

    • for lipid diffusion, lipid: aqueous partition coefficient -- major determinant of drug mobility

      • partition coefficient reflects how easily the drug enters the lipid phase from the aqueous medium.

  •  thickness: length of the diffusion path

Katzung, B. G. Basic Principles-Introduction , in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p 5.

  • Plasma protein-bound drugs cannot permeate through aqueous pores

  • Charged drugs will be influenced by electric field potentials {membrane potentials, especially important in renal, trans-tubular drug transport}

  • Animation


Lipid diffusion 

  • The membrane lipid bilayer is the most important barrier for drug permeation since there are many lipid barriers separating body compartments 

    • Lipid: aqueous drug partition coefficients describes the ease with which a drug moves between aqueous and lipid environments

    • Ionization state of the drug is an important factor: charged drugs diffuse-through lipid environments with difficulty.

      •  pH and the drug pKa, important in determining the ionization state, will influence significantly transport (ratios of lipid-to aqueous-soluble forms for weak acids and bases described by the Henderson-Hasselbalch equation.

        • Uncharged form: lipid-soluble

        • Charged form: aqueous-soluble, not lipid soluble; passes through biological membranes with difficulty

Electron Micrograph (left) and Lipid-Bilayer Model (right)


Lipid-Bilayer with Membrane-Protein

courtesy of Professor Thomas M. Terry, used with permission


Special Carriers

  • Peptides, amino acids, glucose are examples of molecules then enter cells through special carrier mechanisms.

  • Carriers:

    • Active transport--energy requiring

    • Facilitated diffusion--requires the carriers to facilitate transport

    • Aaturable (unlike passive diffusion, which is not saturable)

    • Inhibitable

  • Transport that utilizes an ionic concentration gradient to drive a co-transported molecule (same direction)  is classified as "symport" 

  • Animation



Transport Systems
  • Although carrier-mediated processes are involved in the excretion of certain drugs, most drugs do not require specific transport mechanisms to enter the cell since they diffuse directly through the lipid bilayer.  Accordingly, the "lipid solubility" of the drug as well as the magnitude of the trans-membrane  drug concentration are major factors that determine drug pharmacokinetic behavior.

  • In the diagram above, the drug (transported molecule) traverses the membrane by simple diffusion.  Certain important membrane proteins such as the nicotinic cholinergic receptor are examples of proteins that are themselves ion channels.  The electric chemical gradient refers to the membrane potential, for example -90 mv, which can serve as the driving force in "symport" reactions.

Above figure courtesy of Professor Steve Wright and the University of Arizona (c), used with permission


 Endocytosis and exocytosis


  • Endocytosis Definition: transport of solid matter or liquid into the cell utilizing a coated vacuole or vesicle.

  • Exocytosis Definition: Transport of materials out of a cell using a vesicle that first engulfs the material and then is extruded through an opening in the cell membrane.

  • Entry into cells by very large substances (e.g., iron vitamin B12 -- each complexed with its binding protein -- movement across intestinal wall into the blood)
  • Exocytosis examples: neurotransmission--
    • activation of nerve endings:
      1. storage vesicles fusion with cell membrane
      2. diffusion of contents into extracellular region
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