Advanced metabolism

Question 1

What are the cytochrome P450 enzymes responsible for?

Answer 1

They are responsible for detoxifying and metabolizing foreign compounds and drugs.

Question 2

If you take a drug what is going to happen to it?

Answer 2

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.

Question 3

Answer to what happens when you take a drug?

Answer 3

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.

Question 4

What is a therapeutic window and why is it important?

Answer 4

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.

Question 5

How are medications with a narrow or small therapeutic window administered?

Answer 5

Medication with a small therapeutic window must be administered with care and control, frequently measuring the blood concentration of the drug, to avoid harm.

Question 6

What leads to drug failure?

Answer 6

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.

Question 6

What leads to drug toxicity?

Answer 6

-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.

Question 6

What is Therapeutic index?

Answer 6

The ratio between the lethal or toxic dose and the effective dose shows the normal range of pharmacological effects.

Question 7

Why should the effective dose be lower than the toxic dose?

Answer 7

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).

Question 8

Why is a high therapeutic index is ideal?

Answer 8

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

Question 9

What is the therapeutic index ratio?

Answer 9

TI=(minimum toxic dosage)/(minimum effective dosage)

Question 10

What is drug clearance?

Answer 10

The removal of drugs by all processes from the biological system.

Question 11

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?

Answer 11

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.

Question 12

Where does drug elimination occur?

Answer 12

Kidneys whereby water-soluble molecules are removed after biotransformation and being broken down into smaller molecules.

Question 13

Why are kidneys not capable of eliminating lipophilic chemicals?

Answer 13

Lipophilic agents must be made water soluble to be cleared by kidneys. They are structurally altered through biotransformation.

Question 14

Which organ has the greatest role in biotransformation and why?

Answer 14

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.

Question 15

Which other organs are involved in biotransformation except the liver?

Answer 15

Intestinal wall, lungs, kidneys, and plasma.

Question 16

How is drug metabolism achieved?

Answer 16

Through phase I and phase II metabolism.

Question 17

How is the concentration of the drug reduced during the first pass?

Answer 17

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.

Question 18

Why is it a problem for drugs to pass through the epithelial cells?

Answer 18

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.

Question 19

how does drug metabolism occur in phase I and phase II?

Answer 19

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.

Question 20

Why are some drugs taken, broken down straight away?

Answer 20

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.

Question 21

In an overdose of acetaminophen, what strategy can be used to decrease the amount of NAPQI produced?

Answer 21

The addition of a precursor molecule GSH can reduce the amount of NAPQI.

Question 21

Acetaminophen (APAP) is metabolised to NAPQI by the inducible metabolizing enzymes CYP2E1 and CYP3A4. What effect does NAPQI have on the body?

Answer 21

NAPQI is a hepatotoxin that damage the liver cells.

Question 22

Which organs have the highest biotransformational capacity?

Answer 22

The liver and the gut mainly process and clear large amounts of the endogenous and xenobiotic chemicals.

Question 23

What happens in phase I metabolism?

Answer 23

Phase I is also known as the oxidative CYP reaction.
-Reduction and hydrolyses are also considered as phase I biotransformation.
-Polar groups are unmasked or added to a molecule, which makes the molecules water-soluble enough to be cleared.

Question 24

What happens in phase II metabolism?

Answer 24

It is a conjugative (makes molecules bigger) CYP process.
-This process will attach a drug covalently to an appropriate functional group. This is were water-soluble compounds are formed.

Question 25

What happens in phase III metabolism?

Answer 25

-The system of efflux pumps excludes water-soluble products of metabolism from the cell to the intestinal fluid, blood, and finally the kidneys.
-Also excludes parent drugs as soon as they are absorbed from the gut.

Question 26

Cytochrome P450 are classified according to what?

Answer 26

Amino acid homology

Question 27

How are CYP enzymes labeled?

Answer 27

E.g CYP3A4
-The number in front of the CYP enzyme represents the family.
-The letter A represents the sub-family.
- The number after the family is an isoform.

Question 28

Only 6 CYPs have a major in drug metabolism. What are they?

Answer 28

-CYP2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4

Question 29

What is a single nucleotide polymorphism (SNPs)?

Answer 29

-A location where individual alleles differ by one base pair.
-A genetic difference that can occur between different individuals.

Question 30

What can SNPs result in?

Answer 30

-Inactivation of enzyme therefore absence of enzyme.
-Over or underproduction of the enzyme.
-The enzyme having an altered function.

Question 31

What is the positive impact of a polymorphism?

Answer 31

The absence of the enzyme would prevent the activation of procarcinogens and would in turn protect against disease.

Question 32

What is the negative impact of a polymorphism?

Answer 32

When the metabolism of a drug does not occur, the drug remains in the body for longer periods of time and therefore causes harm.

Question 33

What is the most highly polymorphic CYP with over 70 allelic variants reported?

Answer 33

CYP2D6

Question 34

What does CYP2D6 metabolize?

Answer 34

B-blockers, antidepressants and opioids.

Question 35

What does an ultrafast metabolizer possess?

Answer 35

2 or 3 copies of the active gene. e.g CYP2A6*1/1

Question 36

What does an extensive metabolizer possess

Answer 36

2 copies of an active gene such as the wild type CYP 2A6*1/1

Question 37

What does an intermediate metabolizer possess?

Answer 37

one active gene and one inactive gene. E.g CYP2A61/4

Question 38

What does a poor metabolizer possess?

Answer 38

2 copies of the inactive gene resulting in no enzyme activity. E.g CYP2A64/4

Question 39

what are the key features of CYPs?

Answer 39

-Multiple binding sites.
-Having the haem group in their active site that contains iron.
-To catalyze oxidation and reduction, the iron undergoes both.
-Cytochrome b5 and P450 oxidoreductase supply electrons.
- CYPs bind and activate haem.

Question 40

How is the CYP structured?

Answer 40

CYPs have 12 a-helix labelled A-L and four B-sheets.