Cell Membrane Transport and Diffusion Mechanisms

Fenestrated Endothelium

• Found in endocrine glands
• Facilitates transfer of hormones and other molecules through pores in the endothelium

Movement of Small Molecules Across Cell Membranes

• Four main ways:
  • Diffusion through lipids
  • Diffusion through aqueous pores
  • Transmembrane carrier proteins
  • Endocytosis

Passive Diffusion

• Major mechanism for drug absorption
• Driven by concentration or electrochemical gradient
• Follows Fick's first law of diffusion: molecules diffuse from a region of higher concentration to lower concentration until equilibrium is reached.

Influence of pH on Passive Diffusion

• Governed by:
  • Dissociation constant (pKa) of the drug
  • Lipid solubility of the unionized drug
  • pH of the absorption site
• Most drugs are weak acids or bases that exist in both ionized and non-ionized forms, with non-ionized molecules being more lipid soluble and diffusing more easily.
• Transmembrane distribution of a weak electrolyte is determined by its pKa and the pH gradient across the membrane.

Weak Acids, Bases and Absorption

• Weak acids:
  • Very weak acids (pKa > 8) are mostly unionized at all pH values, leading to rapid absorption independent of GI pH.
  • Acids with pKa between 2.5 and 7.5 are best absorbed in acidic conditions of the stomach (pH < pKa) where they are predominantly unionized.
  • Stronger acids with pKa < 2.5 are ionized across the entire GIT pH range and are poorly absorbed.
• Weak bases:
  • Very weak bases (pKa < 5) are mostly unionized at all pH values, leading to rapid absorption independent of pH.
  • Bases with pKa between 5 and 11 are best absorbed in the more alkaline conditions of the intestine (where they are predominantly unionized).
  • Stronger bases with pKa > 11 are ionized across the entire GIT pH range and are poorly absorbed.

Brief History of Pharmacology

• Medicaments have been used for treating diseases for a long time.
• Traditional knowledge, empirical information, formed the basis of early medicine.
• Claudius Galen (AD 129–200): First attempted to consider the theoretical background of pharmacology.
• Theophrastus von Hohenheim (1493–1541), aka Paracelsus: Rejected irrational concoctions and mixtures of medieval medicine.
• Johann Jakob Wepfer (1620–1695): First to verify pharmacological and toxicological actions through animal testing.

Drug Nomenclature

• Drugs have three categories of names:
  • Chemical name: describes the substance chemically
  • Non-proprietary (generic) name: name accepted by a scientific body
  • Proprietary (Brand) name: name assigned by the manufacturer

Pharmacokinetics

• Deals with absorption, distribution, metabolism, and excretion of drugs.
• Drug concentration at the site of action depends on all these processes.
• All pharmacokinetic processes involve drug passage across membranes.

Movement of Drug Molecules Across Cell Barriers

• Cell membranes act as barriers between the body's aqueous compartments.
• For drugs to pass from one side of a cell to the other, they need to cross at least two cell membranes.
• Vascular endothelium: Gaps between cells are packed with proteins that act as filters.
• Some organs (e.g. CNS, placenta) have tight junctions between cells, preventing harmful molecules from entering.
• Other organs (e.g. liver, spleen) have discontinuous endothelium, allowing free passage between cells.

Carrier Mediated Transport

• Involves binding of the drug to specific receptors on the membrane for translocation into the cytoplasm.
• Characteristics:
  • Selectivity
  • Competitive inhibition by chemical congeners
  • Requires energy
  • Saturability
  • Movement against electrochemical gradient
• Active transport: movement against the concentration gradient
• Facilitated diffusion: movement along the concentration gradient but at a faster rate than simple diffusion

Filtration or Pore Transport

• Passage through the water-filled pores in membranes.
• Accelerated by the hydrodynamic flow of water under hydrostatic or osmotic pressure gradient.
• Requires water solubility and a smaller molecular size than the pore diameter.

Drug Absorption

• Rate at which a drug leaves its administration site and the extent to which this occurs.
• Bioavailability: extent to which a drug reaches its site of action or a biological fluid from which the drug has access to its site of action.
• Absorption occurs through one or a combination of the processes described earlier.

Factors That Modify Absorption

• Drug solubility at the site of absorption
• Dosage form
• Local conditions at the site of action
• Drug concentration at the site of absorption
• Circulation to the site of absorption
• Area of the absorbing surface
• Route of administration

Drug Distribution

• Process by which absorbed drug or drug directly introduced into the circulation is carried to various interstitial and cellular fluids.

Pulmonary Excretion

• Any volatile material can be excreted through the lungs, regardless of the route of administration.
• Rate of excretion depends on respiration rate, pulmonary blood flow, and gas solubility in blood.

Sweat and Saliva Excretion

• Depends on diffusion of un-ionized lipid-soluble forms across gland epithelial cells.
• Quantity excreted is determined by the drug's pKa and the pH of the secretions.
• Excretion in sweat can cause skin reactions.
• Substances excreted in saliva are usually swallowed.

Excretion in Milk

• Concentration of drugs in milk depends on:
  • Amount of drug in maternal blood
  • Lipid solubility of the drug
  • Drug's degree of ionization
  • Extent of its active excretion
• Milk is more acidic (pH 6.5) than plasma, meaning basic drugs are more concentrated in this fluid.

Clinical Significance of Drug Excretion

• Excretion determines how long a drug remains in the body, influencing its duration of action.

Routes of Drug Administration

• Drugs are administered for local or systemic effects.
• The choice of route depends on:
  • Target tissue
  • Physico-chemical properties of the drug
  • Disease state

Systemic Routes of Administration

• Oral ingestion: Administration of drugs through the mouth, mostly for systemic effects.