Pharmacokinetics is the way that the body deals with a drug - how that drug moves throughout the body, and how the body metabolizes and excretes it.  The factors and processes involved in pharmacokinetics must be considered when choosing the most effective dose, route and schedule for a drug's use.

The four processes involved in pharmacokinetics are:

Absorption:  The movement of a drug from its site of administration into the blood.

• Several factors influence a drug's absorption:

  • Rate of Dissolution:  the faster a drug dissolves the faster it can be absorbed, and the faster the effects will begin.

  • Surface Area:  Larger surface area = faster absorption.

  • Blood Flow:  Greater blood flow at the site of drug administration = faster absorption.

  • Lipid Solubility:  High lipid solubility = faster absorption

  • pH Partitioning:  A drug that will ionize in the blood and not at the site of administration will absorb more quickly.

Distribution:  The movement of drugs throughout the body.

Metabolism:  (Biotransformation) The enzymatic alteration of drug structure.

Excretion:  The removal of drugs from the body.

As a drug moves through the body, it must cross membranes.  Some important factors to consider here then are:

• Body's cells are surrounded by a bilayer of phospholipids (cell membrane).

• There are three ways that a substance can cross cell membranes:

  • Passing through channels and pores: only very small molecules can cross cell membranes this way.

  • Transport Systems:   Selective carriers that may or may not use ATP.

  • Direct Penetration of the Cell Membrane:  Remember way back in Chem 120A when we were taught that principle of "like dissolves like?"  Keeping the structure of the cell membrane in mind (2 layers of phospholipids with long hydrophobic tails on the outside), we can infer that drugs that are lipid soluble will pass through the membrane.  Polar molecules (like H₂0) and ions are not lipid soluble.

    • pH Dependent Ionization:  an acid will be unionized in acidic media, but will ionize in an alkaline environment.  Therefor, an acid in an alkaline media will carry a charge and be unable to directly penetrate cell membranes.  (A base will ionize in acidic environments).

    • Ion Trapping (pH partitioning):  Drugs will accumulate on which-ever  side of a membrane that favors their ionization.  So keeping in mind that an acid will ionize in an alkaline environment, and a base will ionize in an acidic environment  we can determine in which environment a drug will accumulate.

Routes of Drug Administration

Intravenous

*No barriers to absorption since drug is put directly into the blood.

*There is a very rapid onset for drugs administered intravenously.  This can be advantagous in emergency situations, but can also be very dangerous.

*This route offers a great deal of control in respect to drug levels in the blood.

*Irritant drugs can be administer by the IV route without risking tissue injury.

*IV drug administration is expensive, inconvenient and more difficult than administration by other routes.

*Other disadvantages include the risk of fluid overload, infection, and embolism.  Some drug formulations are completely unsafe for use intravenously.

Intramuscular:

*Only the capillary wall separates the drug from the blood, so there is not a significant barrier to the drug's absorption.

*The rate of absorption varies with the drug's solubility and the blood flow at the site of injection.

*The IM route is uncomfortable and inconvenient for the patient, and if administered improperly, can lead to tissue or nerve damage.

Subcutaneous

*Pretty much the same characteristics as the IM route.

Oral

*Two barriers to cross: epithelial cells and capillary wall.  To cross the epithelium, drugs have to pass through the cells.

*Highly variable drug absorption influenced by many factors:  pH, drug solubility and stability, food intake, other drugs, etc.

*Easy, convenient, and inexpensive.  Safer than parenteral injection, so that oral administration is generally the preferred route.

*Some drugs would be inactivated by this route.

*Inappropriate route for some patients.

*May have some GI discomfort, nausea and vomiting.

*Types of oral meds = tablets, enteric-coated, sustained-release, etc.

Topical, Inhalational agents, Suppositories

Three major controlling factors:  

Blood Flow to Tissues:  rarely a limiting factor, except in cases of abscesses and tumors.

Exiting the Vascular System:  Occurs at capillary beds.

Typical Capillary Beds - drugs pass between cells

The Blood-Brain Barrier-  Tight junctions here, so drugs must pass through cells.  Must then be lipid soluble, or have transport system.

Placenta - Does not constitute an absolute barrier to passage of drugs.  Lipid soluble, nonionized compounds readily pass.  

Protein Binding:  Albumin is most important plasma protein in this respect.  It always remains in the blood stream, so drugs that are highly protein bound are not free to leave the bloodstream.  Restricts the distribution of drugs, and can be source of drug interactions.

Entering Cells:  some drugs must enter cells to reach sites of action.

 

Metabolism

Hepatic Drug-Metabolizing Enzymes:  most drug metabolism in the liverperformed by the hepatic microsomal enzyme system.

Therapeutic Consequences of Drug Metabolism

Accelerated Renal Drug Excretion:  The most important consequence of drug metabolism is the promotion of renal drug excretion.  Metabolism makes it possible for the kidney to excrete many drugs that it otherwise could not.

Drug Inactivation

Increased Therapeutic Action: Metabolism may increase the effectiveness of some drugs.

Activation of Prodrugs:  A prodrug is a compound that is inactive when administered and made active by conversion in the body.

Increased or Decreased Toxicity

Special Considerations in Drug Metabolism

Factors that influence rate of metabolism:  

Age:  Hepatic maturation doesn't occur until about a year old.

Induction of Drug-Metabolizing Enzymes:  Some drugs can cause the rate of metabolism to increase, leading to the need for an increased dosage.  May also influence the rate of metabolism for other drugs taken at the same time, leading to a need for increased dosages of those drugs as well.

First-Pass Effect:  Hepatic inactivation of certain oral drugs.  Avoided by parentaral administration of drugs that undergo rapid hepatic metabolism.

Nutritional Status

Competition between Drugs

Excretion

Renal Drug Excretion

Steps:

Glomerular Filtration

Passive Tubular Reabsorption: drugs that are lipid soluble undergo passive reabsorption from the tubule back into the blood.

Active Tubular Secretion

Factors that Modify Renal Drug Excretion

pH Dependent Ionization:  manipulating urinary pH to promote the ionization of a drug can decrease passive reabsorption and hasten excretion.

Competition for Active Tubular Transport

Age:  Infants have a limited capscity to excrete drugs.

Nonrenal Routes of Drug Excretion

Breast Milk

Bile, Lungs, Sweat and Saliva

Plasma Drug Levels

Clinical Significance of Plasma Drug Levels:  It is often not possible to measure concentration of a drug at the site of action.  There is a direct correlation between therapeutic and toxic responses and the amount of drug present in the plasma.

Two Plasma Drug Levels Defined:  

Minimum Effective Concentration:  the plasma drug level below which therapeutic effects will not occur.

Toxic Concentration

Therapeutic Range:  The objective of drug dosing is to maintain plasma drug levels within the therapeutic range.  Located between the MEC and the toxic concentration, so a narrow therapeutic range makes a drug difficult to administer safely.

Single Dose Time Course

Drug Half-Life:  the time required for the amount of drug in the body to decrease by 50%.  Determines the dosing interval.  Not all drugs adhere to the half-life principle.  Instead, some decline at a constant rate.

Drug Levels Produced with Repeated Doses

The Process by Which Plateau Drug Levels Are Achieved:  When the amount of drug eliminated between doses equals the dose administered, average drug levels will remain constant and plateau will have been reached.

Time to Plateau:  Plateau will be reached in approximately four half-lives.

Techniques for Reducing Fluctuations in Drug Levels:    Two methods of drug administration can be used to help reduce fluctuations - Continuous infusion, and reduction of dosage size and interval.

Loading Doses Versus Maintenance Doses:  When plateau must be reached quickly, large initial dose may be given (loading dose).  Plateau maintained by giving smaller doses (maintenance dose).

Decline from Plateau:  When drug administration is discontinued, most (94%) of the drug in the body will be eliminated over an interval equal to four half-lives.

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