Advanced metabolism Flashcards
(45 cards)
What are the cytochrome P450 enzymes responsible for?
They are responsible for detoxifying and metabolizing foreign compounds and drugs.
If you take a drug what is going to happen to it?
The obvious reason why you take a tablet (foreign substance) is that you want it to be effective, eg relieving pain, you want it to show a medical effect in relieving you of pain. So therapeutic consequence is required, so it has to be taken up and go to where it is supposed to work.
Answer to what happens when you take a drug?
Drugs are mostly consumed orally but are not always injected in muscle tissues or veins. When a tablet is consumed lots of processes are activated in the human body. Once you take it, the pill goes into your stomach acid and to the gastric intestinal tract where it might get absorbed. The enzymes that metabolize drugs will be induced. Then the tablet is transported by passive diffusion. Most drugs are weak bases, and are therefore charged in the stomach (pH 1) – absorption from the stomach is low. In the small intestine (pH 7), most drugs are unionized and diffuse through the gut wall.
What is a therapeutic window and why is it important?
A therapeutic window is a drug that is the range of drug dosages that can treat disease effectively without having toxic effects.
It is important because it provides:
* Provides a guide to the “most efficient” drug concentration i.e. the most beneficial pharmacodynamic effect for the minimum side effects.
* Provides a guideline as to whether the drug is within the appropriate concentration range.
How are medications with a narrow or small therapeutic window administered?
Medication with a small therapeutic window must be administered with care and control, frequently measuring the blood concentration of the drug, to avoid harm.
What leads to drug failure?
Decreasing the drug dosage will start off as being effective and then the drug will stop being effective leading to drug failure.
-The reason why the other drug is failing could be, that it is extracted very effectively after binding to proteins.
-Or there might be another drug in the system that is highly metabolized, so there will be more enzymes induced and the rate at which the drug is metabolized will be higher.
-Change in diet and other diseases.
-Poor drug absorption.
-Binding of drug to proteins.
-Rapid removal from target cells.
What leads to drug toxicity?
-When increasing the dosage, it becomes effective until a certain point when it starts to become toxic.
-A low metabolic rate means your body does not get enough time to metabolize the drug.
-Having another drug in your system that might cause other
enzymes to be activated that do not interact with that particular drug and this leads to the inhibition of CYP 450 enzymes.
-Change in diet and other diseases.
What is Therapeutic index?
The ratio between the lethal or toxic dose and the effective dose shows the normal range of pharmacological effects.
Why should the effective dose be lower than the toxic dose?
You want a low dose at which the drug is effective and a very high dose at which the drug is toxic to have an ideal therapeutic window in which the drug can be safely used (a wide Therapeutic window because a narrow one is dangerous).
Why is a high therapeutic index is ideal?
The larger the therapeutic index (TI), the safer the drug is. This is because a high TI enable the drug concentrations to stay in the therapeutic window for a longer period of without it reaching the toxic level
What is the therapeutic index ratio?
TI=(minimum toxic dosage)/(minimum effective dosage)
What is drug clearance?
The removal of drugs by all processes from the biological system.
Whether or not a metabolite retains some therapeutic effect, it will usually be removed from the cell faster than the parent drug and will eventually be excreted in urine and feces. Why?
If biotransformation is taking place whether it be in its active form, the metabolites will be cleared faster than the parent drug. This is because metabolites are water soluble.
Where does drug elimination occur?
Kidneys whereby water-soluble molecules are removed after biotransformation and being broken down into smaller molecules.
Why are kidneys not capable of eliminating lipophilic chemicals?
Lipophilic agents must be made water soluble to be cleared by kidneys. They are structurally altered through biotransformation.
Which organ has the greatest role in biotransformation and why?
The liver is the primary site of drug metabolism and acts to detoxify and facilitate the excretion of xenobiotics by enzymatically converting lipid-soluble compounds to more water-soluble compounds.
Which other organs are involved in biotransformation except the liver?
Intestinal wall, lungs, kidneys, and plasma.
How is drug metabolism achieved?
Through phase I and phase II metabolism.
How is the concentration of the drug reduced during the first pass?
The process is a result of absorption, generally by the gut wall followed by filtration through the liver in turn resulting in only a portion of the original amount entering the bloodstream and reaching the target tissue.
Why is it a problem for drugs to pass through the epithelial cells?
The presence of efflux proteins can limit drug absorption from the intestinal epithelial cells into the bloodstream. When drugs are administered orally, they must pass through the intestinal epithelium to reach systemic circulation. If efflux proteins are highly expressed in the intestine, they can actively pump drugs out of the epithelial cells back into the intestinal lumen, reducing their bioavailability.
how does drug metabolism occur in phase I and phase II?
The drug travels to the liver via the hepatic portal vein and that is where phase I and II metabolism occurs. The drug is metabolized by the hepatic enzymes. This is phase I, those CYP450 enzymes. From there on you have the transferases that are part of phase II. They transfer soluble conjugates onto the molecule. E.g These water-soluble molecules are more likely to be excreted or inactivated.
Why are some drugs taken, broken down straight away?
Some of the CYPs will already be there because they have been induced before and because they have an endogenous function. They turnover natural compounds.
In an overdose of acetaminophen, what strategy can be used to decrease the amount of NAPQI produced?
The addition of a precursor molecule GSH can reduce the amount of NAPQI.
Acetaminophen (APAP) is metabolised to NAPQI by the inducible metabolizing enzymes CYP2E1 and CYP3A4. What effect does NAPQI have on the body?
NAPQI is a hepatotoxin that damage the liver cells.
