Drug Inactivation and Elimination

Question 1

First Order Kinetics

Answer 1

○ Exponential process where a constant fraction (50%) of free drug in blood is removed at each time interval
○ Half life- time it takes for plasma concentration to fall to half of its peak level
Faster clearance at higher blood concentrations

• Most psychoactive drugs follow first order kinetics

Question 2

Zero Order Kinetics:

Answer 2

○ Constant rate of clearance over time, not affected by blood concentration (linear model)
i.e. alcohol (1 pint of beer- 33g/ hour)

Question 3

Drug Metabolism:

Answer 3

• Biotransformation of drugs occurs primarily in the liver and is mediated by microsomal enzymes
○ Becomes more ionized, inactive
• Cytochrome P450 enzyme family metabolize a variety of psychoactive compounds
○ Selective for psychoactive compounds, but not selective for compounds within that classification
• Ability of an enzyme to alter a drug depends on the formation of the enzyme drug complex
○ E + D E * D (Enzyme drug complex) ——> M (metabolite)+ E
• Products of the drug enzyme complex can be
○ Inactive metabolite (no effect)
○ Active metabolite (bind to receptors, causes an effect)
○ Both
Drug molecules are modifies in 2 ways- non-synthetic reactions and synthetic reactions

Question 4

Non-Synthetic Reactions:

Answer 4

• Type I/ Phase I
• Parent drug is modified by oxidation, reduction, or hydrolysis
• Products can be active or inactive (sometimes they are more active than the parent drug)
• In general, drugs that undergo non-synthetic reactions are not eliminated before undergoing a conjugation reaction
i.e. Aspirin (acetylsalicylic acid) — (hydrolysis- cleaved by adding water)—-> salicylic acid (active)

Diagram

Question 5

Synthetic Reactions:

Answer 5

• Conjugations/ Type II/ Phase II
• Chemical coupling (promoted by enzymes) of the drug with a molecule provided by the body
• Most common synthetic reaction is conjugation with glucuronic acid (derived from glucose)
Chemical now inactive, can be excreted

Diagram

Question 6

Factors Influencing Drug Metabolism:

Answer 6

Enzyme induction
Enzyme inhibition
Drug competition
Genetic factors
Environmental factors

Question 7

Enzyme induction

Answer 7

○ Drugs can cause an increase in liver enzymes
○ Results in reduced drug effect
i.e. Excessive amounts of nicotine results in upregulation of nicotine degrading enzymes, results in tolerance to nicotine as well as cross tolerance to antidepressants and caffeine (enzymes that degrade nicotine aren’t specific to only nicotine)

Question 8

Enzyme inhibition

Answer 8

○ Drugs can cause a decrease in liver enzymes
○ Results in increased drug effects
i.e. Monoamine oxidase inhibitors (antidepressants) inhibit enzymes that break down monoamines. Taken orally so they act in the periphery as well as in the brain, inhibits enzymes that break down other drugs too (opiates, alcohol…etc)

Question 9

Drug Competition

Answer 9

○ If taken at the same time, drugs can compete with each other to access the same binding site, can cause a reduced effect of one drug and an enhanced effect of the other.
i.e. Alcohol and barbiturates

Question 10

Genetic Factors

Answer 10

○ Asian population has difficulty breaking down acetaldehyde (intermediate in alcohol breakdown)
Gender- stomach enzymes for alcohol more effective in males

Question 11

Environmental Factors

Answer 11

Nutrition and age compromises liver function

Question 12

Renal Excretion:

Answer 12

• Drugs are eliminated from the body primary as metabolites, most important organ of elimination is the kidneys (urine)
  
  • Kidneys filter end products of metabolism (urea, uric acid, drugs) and maintain appropriate levels of water, sugar, sodium, potassium, and chloride
  • Ionization of drugs by liver metabolism makes drugs less lipid soluble, and thus less likely to be reabsorbed into the general circulation