Drug metabolism & elimination -4

Question 1

Elimination

Answer 1

any process that inactivates or leads to the removal of an active drug from the body. Elimination is typically more efficient for hydrophilic (water soluble or polar) drugs.
Hepatic metabolism, renal excretion, biliary & fecal excretion, lung metabolism, plasma & extracellular enzymes, spontaneous degradation, alveolar expiration.

Question 2

Total body clearance (TBC)

Answer 2

a theoretical measure of the plasma volume that is cleared of drug during any given period of time- expressed as a volume of plasma that a cleared completely of drug. Defined as the product of the apparent volume of distribution and the elimination rate constant (Ke). TBC= Vd X Ke.
Equivalent to the sum of individual organ clearance rates for first-order elimination processes. TBC= C renal + C hepatic + …

Question 3

Renal clearance

Answer 3

involves 3 distinct processes for many drugs: glomerular filtration, tubular secretion, tubular reabsorption.
In the calculation of renal drug clearance, TR is subtracted, since this process removes drug from provisional urine.
CL renal= GF + TS - TR.
Many drugs are eliminated predominantly or entirely by renal clearance. Clearance can be altered markedly by certain diseases or disorders.

Question 4

Glomerular filtration

Answer 4

of free (unbound) drug is determined by renal perfusion or glomerular filtration rate (GFR). Proportional to cardiac output, not affected by net drug charge, reduced for protein bound drugs.

Question 5

Tubular secretion

Answer 5

is an active carrier-mediated process primarily in the proximal tubules. Distinct carriers for acidic and basic drugs. Opportunity for drug interactions.

Question 6

Tubular reabsorption

Answer 6

is a passive diffusion-driven process that depends primarily on net drug charge. Neutral form is reabsorbed preferentially (charged form less permeant). Strongly affected be changes in urinary pH (opportunity for intervention).

Question 7

Hypoalbuminemia

Answer 7

age, burns, hepatic disease, nutritional.

Decreases drug protein binding leads to increases filtration= increased clearance.

Question 8

Cardiac insufficiency

Answer 8

shock, cardiomyopathy, ect.

Decreased GFR leads to decreased clearance.

Question 9

Acid base imbalances

Answer 9

respiratory or metabolic origin.

Altered pH leads to a change in drug charge leading to change in tubular reabsorption.

Question 10

Hepatic drug clearance

Answer 10

involves a wide spectrum of enzyme catalyzed biotransformation reactions. Liver is well suited for drug metabolism- high blood flow, gaps in endothelial cells, unusual cytoarchitecture. Effects usefulness of a oral administration.

Question 11

First pass effect- hepatic drug clearance

Answer 11

is the extent to which an orally administered drug is metabolized during its first pass through the portal circulation. Can range from 0-100%. Saturable in some cases.
Drugs with a high first pass effect should be used with caution in animals with hepatic disease.

Question 12

Drug metabolism

Answer 12

can occur in any tissue, but most often is catalyzed in liver. Renders drugs more polar (increased water solubility). Broadly sub-divided into two categories. Phase 1 reactions and phase 2 reactions.
Drugs that are metabolized by the same family of hepatic CYP isoymes can compete with one another. Drugs can act as inhibitors or as inducers of CYP izozymes.

Question 13

Phase 1 reations

Answer 13

catalyzed by cytochrome P enzymes. 
a) four families (1-4)
b) six sub families (A-F)
c) up to 20 isoenzymes (1-20)
produces chemical modifications of the parents drug. oxidation, reduction, hydrolysis, etc.

Question 14

Phase 2 reactions

Answer 14

coupling reactions of drug with an endogenous substance.

Glucuronidation, sulfation, acetylation, etc.

Question 15

Species/strain differences

Answer 15

cats- poor at glucuronide conjugation (morphine).
dogs- poor acetylation of sulfonamides.
pigs- xylazine.
rabbits- atropine (belladonna alkaloids)

Question 16

Gender differences

Answer 16

hormonal influences

Question 17

Age differences

Answer 17

drug metabolism is generally reduced in young and elderly animals

Question 18

Inhibitors

Answer 18

short (cimetidine) or long acting (chloramphenicol). Disrupts metabolism of other drugs. Prolongs or intensifies drug effects.

Question 19

Inducers

Answer 19

increase activities of selected hepatic enzymes (phenobarbital). Enhances metabolism of other drugs. Shortens or diminishes drug effects.

Question 20

Alternative consequences of drug metabolism

Answer 20

metabolism does not always lead to drug inactivation.
Prodrug activation: conversion of inactive parent drug leads to active metabolite.
Formation of active metabolite: parent drug and metabolite are active.
Lethal synthesis: conversion of nontoxic parents drug into a toxic metabolite.