S3: Drug Metabolism and Elimination Flashcards
What are the two ways drug elimination can be done?
- Metabolism
- Excretion
With drug elimination we are looking at how much of the parent drug is remaining in the body.
Describe metabolism of drugs
- This is when the parent drug will be metabolised to a daughter compound so therefore it is eliminated (the parent drug).
- The majority of these metabolic processes will be aiming to convert the drug from a more lipid soluble version to a more water soluble version.
- The production of more water soluble drugs means that it prevents re-absorption of the drug by the kidney (as drug is unable to move out of renal tubule) hence increases excretion.
- A lot of the metabolism occurs in the liver, where there are a lot of metabolic enzymes. However we do have other enzymes in other parts of the body including our blood stream (e.g. esterases), lung tissue and the intestinal epithelium.
Describe excretion of drugs
- This is the removal of drug/metabolites from the body
- If a drug is more water-soluble it is more easily excreted by the kidney.
- We can be talking about excretion of the parent drug or any of the metabolites produced
- Most drugs will be excreted in urine, more lipid-soluble ones may be excreted through bile/faeces or milk (avoid using the drug if is woman breast feeding otherwise there is a risk on dosing the baby). Some of the water-soluble drugs may come out in other aqueous secretions like sweat, tears, saliva and exhaled air.
Why is drug metabolism and excretion important?
- If the drug hangs around too long, it would affect the dosage and dosing frequency.
- So metabolism and clearance determine the amount of drug available at the site of action.
- If a drug is metabolised and cleared quickly we may have to give a higher dose or make it more frequent. The longer the half-life, the longer it takes to reach steady state, so if a drug has a lower rate of excretion then it will give a longer half-life as it takes longer for our body to remove the drug. Therefore it would mean longer time to reach steady state.
- There is also safety issues to consider.
- We are concerned about the parent drug and about its excretion but we also need to be aware of the metabolites produced, quite often these metabolites can be active or toxic.
- We want to watch out for levels of enzyme activity as we don’t want the metabolites to reach toxic levels. Remember the body handles even isomers differently.
- Also, it is important to aid the design of future drugs.
How is drug metabolism and excretion useful clinically?
If a person has taken a drug and we want to find out which drug, but a few days have already past. The parent compound will have been completely eliminated but the metabolites may still be present. Therefore if we do a blood test looking for substance abuse we can find which drug was taken and the dosage taken even if the parent drug is no longer in their system. We just need to know what metabolites to look for.
Why do most drugs undergo metabolism by liver prior to removal by kidney?
This is in order to increase excretion of the drug.
3 outcomes of drug metabolism
- Most of the time we also assume the parent compound is the one we want to use, so when it gets metabolised we have a loss of or reduced biological activity. i.e. Our parent drug is the one binding to the receptors or inhibiting an enzyme etc. but once it starts to get metabolised and side chains get removed etc. then some of this biological activity is lost.
- Sometimes the parent drug given to the patient is actually inactive and requires a pass through a metabolic pathway in order to become an activated drug. This parent drug is called a pro drug. A common example is ACE inhibitor. This is usually because the active drug is sensitive to enzymes e.g. in GI tract so with a prodrug, it will be active in the right areas.
- Third outcome is that the body does not metabolise the drug at all. These drugs are readily excreted by kidney with no metabolism. Clinically this is useful to know if ordering blood tests.
Describe phase one of drug metabolism
Phase 1 introduces chemically reactive groups.
- It makes the parent compound more reactive by adding a reactive group. A very common example is oxidation, which adds oxygen to the compound making the drug more polar and reactive. This occurs in the liver.
- The cytochrome p450 enzymes are responsible for this (they are a huge superfamily of enzymes in the liver). These enzymes help by binding the drug and a molecule of oxygen.
- A lot of the cytochrome P450 enzymes also have a reductase function, so when you have the molecule of oxygen (O2) one of the atoms is added to the drug (drug is oxidised). The other oxygen atom is reduced to water. So some enzymes can be an oxidase and a reductase.
- There are also other simple reactions in phase 1 like hydrolysis and hydration which generally make the drug more polar and reactive.
Describe phase two of drug metabolism
Phase 2 increases water solubility of drug for excretion.
- They generally do this by adding large side chains in conjugate reactions.
- An example would be glucoronidation (conjugation of drug with glucose).
Describe paracetamol metabolism
- It undergoes phase 2 reactions first.
- Under therapeutic doses, paracetamol will be conjugated with glucose or sulphate to produce inactive (safe) products. These two will then be filtered out and excreted in urine. They are both phase 2 reactions and they occur first.
Describe paracetamol metabolism during overdose
- When a person has an overdose of paracetamol the story is different. This is because all enzymes are saturatable and too much paracetamol will mean eventually the enzymes in the glucose and sulfate conjugation reactions will saturate (phase 2 reactions).
- Then the excess paracetamol will be put through the phase 1 pathway (which is abnormal). It will be metabolised by cytochrome P450 into a toxic compound (Quinone-imine which is really reactive).
- CYP450 is highly expressed in the liver so quinone-imine is produced in the liver during paracetamol overdose and the liver is usually the area of damage.
- If it is a moderate overdose, the body can get over it. The liver does this by conjugating the toxic quinone-imine with glutathione.
This reduces the toxic effects as the resulting product of the conjugation is non-toxic. However this glutathione reaction is also saturatable, so really high paracetamol overdose will lead to the toxic compound accumulate which will damage the hepatocytes. - Alcoholics are more prone to the harmful effects of paracetamol as they tend to have excessive cytochrome P450 (and other CYP isoforms) which breakdown paracetamol. This is a contraindication that we must consider when prescribing to alcoholics and this is a pharmacokinetic consideration.
How does renal elimination affect a drug?
Renal clearance is the volume of plasma cleared of a drug per unit time in one pass through the kidney. The drug is cleared from the blood and will appear in the urine.
- The larger the clearance the quicker it is for the body to remove the drug and the shorter the half-life.
So, if the renal elimination is low, then the plasma half-life will be higher.
- This is important for dosing regimens, steady state etc.
How can plasma (overall) clearance be estimated?
Overall clearance = hepatic clearance + renal clearance
How can age affect drug metabolism and excretion?
- Many drugs tested are applied to adults. However, neonates and the elderly have reduced cytochrome p450 and hence the metobolic activity of the liver is lower.
- The GFR is also lower in neonates and elderly.
- Combining the low p450 and GFR means that a lower dose will need to be given.
- Age also changes fat content, the elderly have increased % of fat content. This links to distribution as a drug that is lipid soluble can be stored in fat then more of the drug will get stored and it will take longer to remove the drug.
How can genetics affect drug metabolism and excretion?
- There are also genetic differences in enzyme activity etc.
- Different ethnic groups have different enzyme activity, e.g. East Asians with alcohol metabolism
