Pharmacokinetics Overview Quiz

Pharmacokinetics

• Pharmacokinetics describes the movement of a drug in the body. It consists of absorption, distribution, metabolism, and excretion.
• Distribution refers to how drugs move from the systemic circulation to the site of action.
• Two factors are main contributors to drug distribution: plasma protein binding and tissue partitioning.
• When studying pharmacokinetics, we study the movement of drug into, through, and out of the body in terms of 4 main characteristics: ADME
  • Absorption
  • Distribution
  • Metabolism
  • Excretion

Plasma Protein Binding

• Many drugs circulate in the bloodstream bound to plasma proteins.
• This binding is reversible.
• The extent of binding depends on the affinity of a particular drug for protein-binding sites.
• Plasma protein binding (PPB) is expressed as a % of the plasma concentration.
  • For example, Warfarin is 99% PPB, meaning 99% of Warfarin in plasma is bound to plasma proteins; the remaining 1% is unbound and free to bind to receptors and be eliminated.

Plasma Proteins

• Albumin is the most important protein for drug binding and binds acidic drugs, including warfarin, NSAIDs, and sulfonamides.
• ß-globulin and acid glycoproteins bind to basic drugs, such as quinine.

### Unbound Drug

• Unbound drug is free in plasma, can bind to receptors, exerts a pharmacological effect, diffuses into interstitial fluid and cells, can be metabolized, and can be filtered at the glomerulus and excreted.

Bound Drug

• Bound drug is bound to plasma proteins, cannot bind to receptors, can't exert a pharmacological effect, cannot move from the plasma compartment, cannot be metabolized, and cannot be filtered at the glomerulus and excreted.

Factors That Affect Plasma Protein Binding

• Concentration of free drug.
• Drug affinity for the binding sites.
  • Based on whether the drug is acidic or basic.
• Concentration of plasma protein.
  • Disease states.
  • Drug-drug interactions due to competition for the same plasma protein binding sites.

Blood-Brain Barrier (BBB)

• The BBB is formed by tight junctions between the continuous layer of capillary endothelial cells, and glial cells that surround the capillaries.
• The BBB inhibits the penetration of polar and ionised molecules into brain neurons.
• This barrier limits access of many drugs to the central nervous system (CNS).

Alteration of the BBB

• Alteration to the permeability of the BBB can affect drug efficacy.
• This can be caused by conditions such as inflammation, bacterial meningitis, bradykinins, and treatment for brain tumors.

Placenta

• The placenta is a selective barrier that protects the foetus from harmful effects of drugs.
• Almost all drugs cross the placenta to a certain extent.
• Some drugs accumulate in the placenta at levels exceeding those in maternal plasma.
• Drug transfer across the placenta depends on:
  • Lipid solubility.
  • Extent of plasma binding.
  • Degree of ionisation.

Bone

• Certain drugs can accumulate in bone by adsorption onto the bone crystal surface and incorporation into the crystal lattice.
  • This includes tetracycline antibiotic, heavy metals (e.g., lead, radium), and bisphosphonates.
• Bone can be a reservoir for the slow release of toxic agents, allowing effects to persist long after exposure.
  • For example, lead or radium can persist in the bone after exposure.

### Volume of Distribution

• The volume of distribution (Vd) refers to the apparent volume into which a drug is distributed.
• Vd is calculated by dividing the total amount of drug in the body by its plasma concentration.
• Drugs with lower Vd tend to be found primarily in the plasma, while drugs with higher Vd are more widely distributed throughout the body.
• Drugs with a Vd greater than the total body volume are not efficiently removed from the body by hemodialysis (blood filtration).

Volume of Distribution Calculation

• Heparin Vd = 0.07L/kg
• Warfarin Vd=0.14L/kg
• Aspirin Vd = 0.17L/kg
• Amoxicillin Vd = 0.3L/kg
• Valproic acid Vd 0.1 – 0.4L/kg
• Paracetamol Vd = 0.9L/kg
• Diazepam Vd = 0.8-1 L/kg
• Fluoxetine Vd = 20-42L/kg