4. Pharmacokinetics I

60/40/20 Rule

Estimates the volume of fluid in each body compartment based on total body weight

• 60% of total weight → total body water

• 40% of total weight → intracellular fluid (ICF)

• 20% of total weight → Extracellular fluid (ECF) → 75% interstitial and 25% intravascular

Drugs are absorbed faster from organs with large ______ _____ and ________ membranes

Drugs are absorbed faster from organs with large surface areas and thinner membranes

1st Pass or Pre-systemic Metabolism

Process through which ORAL drugs lose most of their bioavailability due to pre-systemic metabolism by the gut wall or liver

Bioavailability

The fraction of the given dose that reaches the systemic circulation following administration by any route

Bioavailability of Major Routes of Administration

• Intravenous

• Intramuscular

• Subcutaneous

• Oral

• Mucous membranes

• Rectal

• Inhalation

• Transdermal

• Sublingual

• Intravenous 100%

• Intramuscular 75-99%

• Subcutaneous 75%-99%

• Oral 5-99%

• Mucous membranes ECTREMELY LOW

• Rectal 30-99%

• Inhalation 5-99%

• Transdermal 80-100%

• Sublingual EXCELLENT

Factors Affecting Oral Drug Absorption

• Blood flow to the area, the more the better absorption

• Gastric emptying time; can be increased by gastric stimulants, fatty foods, anticholinergic drugs and pyloric stenosis

• pH of gut: affects ionization and stability of drug

• Food particles that trap drug molecules

• Surface area and thinness of area increases absorption

Factors Affecting Drug Distribution

1. Drug binding to plasma or tissue proteins decreases distribution and excretion

2. Storage of lipophilic drugs in ADIPOSE TISSUE

3. Blood flow to tissues and organs

4. Physical properties

5. Chemical properties: hydrophilic vs lipophilic

6. Capillary permeability

7. Ionization

Describe how plasma protein binding affects distribution

• Why is this no longer an issue in MOST cases

Plasma protein binding such as albumin traps drug molecules in the vascular space and prevents them from reaching the site of pharmacologic action, as well as decreases clearance

• Not an issue anymore because plasma protein # far exceeds #drug molecules → also as free drug increases so does clearance

  • Only a problem if drug clearance is greatly decreased due to kidney or liver disease OR if displaced drug has low TI

Describe Capillary Permeability in terms of drug acess

• Endothelial cells lining blood vessels in the liver have large fenestrations that allow free movement of substances between the blood and the interstitium

• Blood vessels in the brain have endothelial cells with very tight junctions that only allow high lipid solubility substances to pass the BBB

Explain how redistribution terminates drug action

While the drug may distribute initially to one place to have a pharmacological effect, redistribution to other tissues can terminate the effect

• Ex. Thiopental acts rapidly crossing the BBB and causes anesthetic effect, but then it redistributes to muscle, fat, etc and the patient wakes up because the brain concentration decreased

Volume of Distribution formula

Volume of Distribution (Vd) = Dose (D) / Plasma Concentration (Cp)