PK3 - Metabolism Flashcards
What are the two main outcomes of drug metabolism
1) Drug becomes more water soluble = better renal excretion
2) Drug may become inactivated
What is a prodrug? Example?
Its an inactive drug that must be metabolized to its active form once given
ex; enalapril is metabolized into enalaprilat
Are lipid soluble drugs readily excreted? Why or why not?
They are not readily excreted because they can easily diffuse out of the renal tubules through the membranes
What type of drug solubility does the collecting duct favour?
Most water soluble drug molecules are excreted in the CD
What type of drug solubility does the loop of henle favour?
Most lipid soluble drug molecules are reabsorbed into circulation in the LoH
What is the main location of drug metabolism?
Liver
What are the two main types of metabolic reactions?
- Phase 1 = non-synthetic functionalization
- Phase 2 = Biosynthetic CONJUGATION reactions
How does phase 1 metabolism inactive drugs?
-By creating or uncovering reactive groups like -OH, -COOH, -NH2, -SH
-Achieved mainly through oxidation
What is the solubility of phase 1 metabolites
-Usually more water soluble than the parent molecule and usually more chemically reactive
What happens during phase 2 metabolism? What state are they in?
-Attach drug molecule (phase 1 metabolite) to a substance from the diet (ex; AAs)
-This produces drug conjugates that are usully polar, inactive and readily excreted
Where are conjugation enzymes located?
In the cytoplasm
What is the risk of toxic intermediates if a drug only undergoes phase 2 metabolism?
None
What are the dietary components usually used for phase 2 metabolism?
-Glucuronic acid and glutathione are the most common
-Acetic acid, sulfate and AAs are other options
What is special about cats and phase 2 metabolism?
Cats are deficient in conjugating enzymes so drugs have a longer duration of action and achieve higher concentrations
What NORMALLY happens with metabolism of acetaminophen
Normally only a very small amount of it undergoes phase 1 metabolism, and most of it is simply conjugated either to glucuronic acid or sulfate
What happens when there is an overdose of acetaminophen
It overwhelms the conjugation pathways. There is excess drug oxidized by P450 enzymes (phase 1) into highly reactive/toxic intermediate metabolites that damages anything it touches —> leads to liver failure if dose is high enough
What is the intermediate metabolites oxidized in overdose situations?
NAPQI
Normally its conjugated to glutathione to inactivate it which makes it harmless, but when the system is overwhelmed the glutathion stores are depleted
What can you give in an acetaminophen overdose situation?
Administer a source of glutathione (n-acetylcysteine) = minimizes hepatic damage
Do all drugs go through phase 1 and 2 metabolism?
No, they are many different variations of drugs using both/none or one
What factors affect the rate of drug metabolism? (6)
-Enzyme induction and inhibition
-Multidrug therapy
-Distribution
-Age
-Genetics
-Disease
What can induction of metabolic enzymes lead to?
can also cause drug related toxicity depending on whether phase 1 or 2 enzymes are induced
What happens to drug action when you increase rate of metabolism?
It usually decreases drug action
What happens when there is induction of metabolic enzymes? (Specifically related to hepatic enzymes)
Many hepatic metabolic enzymes can increase in number and activity to certain chemical constituents of food; can also happen with some drugs
What happens with inhibition of drug metabolism?
Certain drugs can inhibit P450 activity, mainly by competing for the same enzyme
Can result in elevated circulating levels of concurrently administered drugs
What might happen with multidrug therapy? When is it most common?
-There are a finite number of hepatic enzyme molecules so some enzyme pathways can be saturated
-This is most common when multiple drugs requiring the same metabolic enzyme are administered at the same time. They compete for or inhibit the enzymes.
How does distribution affect drug metabolism?
Drugs bound to plasma proteins/stored in fat arent available for metabolism
What is the effect of age on drug metabolism?
-Neonates/geriatric patients can be relatively deficiency in metabolic capacity
-Hepatic blood flow might be reduced in heart failure which inhibits drug metabolism
What effect can genetics have on drug metabolism?
Levels of drug metabolizing enzymes can very between individuals due to genetic polymorphisms
How does health and disease affect drug metabolism? (3)
-Poor nutrition can cause deficiency in dietary substances needed for conjugation
-Endocrine dz, liver dz, infectious/inflamm dz = inhibition of drug metabolism
-Heart dz can impair blood flow to liver
