Pharmacokinetics 2

Question 1

P-glycoprotein Efflux Pump

Answer 1

• Active Transport of drugs
  
  • Blood-Brain Barrier
    
    • Secretes drug back into lumen of capillary
    • Keeps drug concentrations / exposure in CNS low
  • Intestines
    
    • Secretes absorbed drug back into the lumen of intestine
    • Decreases drug absorption
  • Liver
    
    • Secretes drug into bile canaliculus
    • Active Biliary Secretion
    • Enhances drug elimination
  • Kidneys
    
    • Renal excretion

Question 2

P-glycoprotein Efflux Pump:

Limiting effects

Answer 2

Some drugs act as p-gp inhibitors decreasing the rate of drug efflux

• Ketaconazole
• concurrent administration with cyclosporine increases the oral absorption of cyclosporine

Some dogs have mutations of the gene encoding the p-gp, resulting in decreased expression of functional p-gp

• Ivermecting and loperamide toxicity in some dogs
  
  • increased penetration to the brain
• Decreases drug elimination
  
  • increases drug absorption

Question 3

P-glycoprotein Efflux Pump:

Deficiency

Answer 3

• Increased penetration of drugs into the CNS
  
  • Ivermectin, Loperamide
• Decreased elimination of drugs
  
  • Biliary secretion - vincristine
  • Renal excretion
  • May also be linked to decreased metabolism
• Increased oral absorption of drugs
  
  • Digoxin - Cardiac Disease treatment

Question 4

P-Glycoprotein Deficiency

Answer 4

• Homozygous Normal
  
  • Lowest toxicity
  • Ivermectin toxicity > 2mg/kg
• Heterozygous Mutation
  
  • Increased toxicity
  • Ivermectin Toxic dose ~0.3mg/kg
• Homozygous Mutation
  
  • Highest toxicity
  • Ivermectin toxic dose ~0.12mg/kg
    
    • Heartworm prevention dose: 0.006mg/kg is safe

Question 5

Acid

Answer 5

Proton Donor (H+)

Question 6

Base

Answer 6

Proton acceptor

Question 7

Amphoteric

Answer 7

Capable of acting as an acid and base

Question 8

pKa

Answer 8

pH at which 50% of the drug is ionized

Ionized compounds have poor lipid solubility

pKa does not predict if a compound is an acid or base

Question 9

pH

Answer 9

-log(h+)

can change

Question 10

Drug Ionization

Answer 10

Unionized drug is more lipid soluble and more capable of diffusion through cell membranes

Ionized drug movement across anatomic membranes is restricted due to a positive or negative charge and poor lipid solubility

Question 11

Henderson-Hasslbalch Equation

Answer 11

• Weak Acid
  
  • ionized form favored when fluid pH > drug pKa
  • Unionized form favored when fluid pH < drug pKa
    
    • “acid-acid” an acid in a more acidic environment favors the unionized form and diffusion
• Weak Base
  
  • Ionized form favored when fluid pH < drug pKa
  • Unionized form favored when fluid pH > drug pKa
    
    • “base-base” a base in a more basic environment favors the unionized form and diffusion

Question 12

Ion trapping

Answer 12

differential drug accumulation in tissue compartments with different pH’s due to drug ionization and poor ability of ionized drug to diffuse across lipid membranes