Drug Metabolism (2) PDF

This is part two of the pharmacokinetics and pharmacodynamics. And this is very much about drug metabolism or the other posh name for it is "biotransformation". So basically the drug is being reduced or removed from the body. So metabolising enzymes are involved in the process. Metabolism can ca...

This is part two of the pharmacokinetics and pharmacodynamics. And this is very much about drug metabolism or the other posh name for it is "biotransformation". So basically the drug is being reduced or removed from the body. So metabolising enzymes are involved in the process. Metabolism can cause the following. It's either converts to water soluble forms that can be eliminated, which happens in most cases, usually via the kidneys or the gut. It can inactivate drugs, so decrease the effect of them, or it can actually activate drugs and increase their effect. For example, in the case of a prodrug like omeprazole. And this is it in a very nice little diagram. So it's either renal elimination in urine or biliary elimination in stools. So just depending which organ it's going to go through. So metabolism is the process by which drugs are neutralised and eliminated from the body. The process by which the body changes the chemical structure of a drug to another form is called a metabolite. It's an enzymatic conversion of one chemical compound drug to its metabolite. And the metabolite in most cases should be more water soluble so that it can actually be easily excreted. IMS 1 TBL 5: Drug Metabolism (2) The major organ for this process of metabolism is the liver. Metabolising enzymes are involved in the process. And metabolism can cause the following: it can convert to water soluble form that can be eliminated. It can inactivate drugs or activate drugs. So, difference between zero order and first order kinetics. You really don't need to know too much about this. It's just that first order kinetics are very, very predictable, the half life: So how long the drug will last in the body is very easily predictable and it's very useful for a drug with a narrow therapeutic index, so where there's a very small difference between the plasma levels of just actually working, and toxicity, such as in carbamazepine, phenytoin or lithium. And the British National Formulary (BNF) will have the target treatment serum levels for many of the narrow therapeutic index drugs. So phase one's reactions are simple chemical reactions. Sometimes reactions in phase one can inactivate a drug before phase two. So phase one, hydrolysis of procaine, which is a local anaesthetic, inactivates the drug. Sometimes reactions in phase one can turn an inactive pro-drug into an active one. Sometimes reaction can turn a harmless chemical into a toxic one. IMS 1 TBL 5: Drug Metabolism (2) And phase one reactions involve a group of oxidase enzymes called oxidase cytochrome p450 enzymes. And these enzymes are responsible to unmask and introduce polar groups, i.e. more water soluble, making it a more water soluble drug. The process is via oxidation, which is the most common. Reduction, and hydrolysis. Hydrolysis is where it adds a water molecule on. And many hepatic drug metabolising enzymes, including the cytochrome enzymes are embedded in smooth endoplasmic reticulum. And to reach those, the drug must cross the plasma membrane. So phase two reactions. These occur mainly in the liver. And they involve conjugation, which is sticking two bits of molecules together to increase water solubility of the drug with a polar moiety functional group, i.e. that it's a plus or a minus when you look at it as an ion. The process is via glucuronidation, which is the most common. Other ways are acetylation, sulfation, and glutathione. So introduction of a hydrophilic polar endogenous species, such as glucuronic acid or sulphate the drug molecule makes it more water soluble. Slow acetylator phenotypes which are patients deficient in acetylation capacity IMS 1 TBL 5: Drug Metabolism (2) may have prolonged or toxic response to normal doses of certain drugs because of decreased rates of metabolism. This happens with certain drugs such as isoniazid, which is used in tuberculosis sulphonamides, which are a kind of antibacterial, and hydralazine, which is a blood pressure reducing agent. Paracetamol goes straight to phase two and is conjugated with glutathione and it can be a problem in overdose. Whereas the limited supply of the conjugate substrate leads to hepatotoxicity. So basically your body's got a very limited amount of the glutathione available and if they take in a very large dose, it gets used up within about 24 to 48 hours and the patient goes into liver failure within about four days of a major overdose of paracetamol. This is just saying that the liver is where most of your metabolism happens. And there is something called the first pass effect in the liver. Where this basically reduces down the amount of activity of the drug if it has to go through the liver in the first place. So, looking at some of the liver function tests So when you've been ordering bloods. You have AST (aspartate aminotransferase). And the other enzymes that you're looking at, which could result from liver damage is ALP, IMS 1 TBL 5: Drug Metabolism (2) alkaline phosphatase and GGT, which is the gamma glutamyl transferase. So in patients, alcoholics, for example, the GGT is widely out of kilter from normal. Basically both the ALP and GGT, are the hepatobiliary enzymes that are increased in liver damage. Also, bilirubin increases as bilirubin is metabolised and excreted in the liver and albumin decreases as it synthesised in the liver. So when there is damage, there's less production. So severe alcoholics will have reduced albumin, so less ability to soak up drugs that are protein bound, and leading to toxicity for the body. So a big one that we really need to know of. You don't need to know the structure, but the enzyme inducer is cytochrome p450. It's this big one that around about 70% of drugs are metabolised by and it will increase the metabolic metabolic activity of the enzyme, which speeds up the breakdown and it will reduce the actual effect of the drug. So you will have seen a lot of these common enzyme inducing drugs. So rifampicin, which is used to treat TB. Anti-epileptics, such as phenytoin, carbamazepine and phenobarbital. Griseofulvin for antifungals; not used very often anymore. Chronic alcohol. Cigarette smoking. And St John's Wart, which is used particularly in Germany actually, for treatment of mild to moderate depression. IMS 1 TBL 5: Drug Metabolism (2) It is a herb and we are not actually sure of how many milligrams of the active drug are in it. So that one can cause a bit of a problem. And you'll see if you look in the leaflet, patients are told if they're on these, they have to be much more careful. And then some of the drugs that are indicated there. And as you can see, disulfiram, at the very bottom there is used to treat alcoholism. So they will end up feeling extremely sick if they drink alcohol. It's called Antabuse: the brand name for it in this country, to help alcoholics get off of alcohol. Grapefruit juice is in there as well in that with simvastatin. Grapefruit juice will actually interact and can cause lots of problems. So first pass metabolism. This is where the drug goes straight through into the liver or other metabolising organs, because you can have it metabolised in the lungs and in various other places. So, for example, in the lungs, the bronchial mucosa actually metabolise prostaglandins. In the GI tract, Penicillin and insulin are metabolised and in the liver propranolol, IMS 1 TBL 5: Drug Metabolism (2) glyceryl trinitrate, labetalol, pethidine are all examples of things metabolised. As you see from the second bullet point, sometimes the result of the first pass metabolism means that only a small proportion of the drug reaches the circulation and therefore its intended target tissue. And the majority of drugs metabolised by the liver with high fast metabolism such as morphine, buprenorphine, diazepam, propranolol, lidocaine (which is used as an anaesthetic) and midazolam. This was just to show you an example. So oestrogen, if its given orally, only 15% of the dose actually enters the blood. You can see that 100% the dose going into the stomach when they swallow it and as it goes through the gut and then through the liver, only 15% of the dose enters the blood. So they've actually developed a topical version, so, a gel, oestrogen gel, and you basically need a much lower dose for it to work. Just rub it onto the skin and therefore has a lower risk of cancer because you are able to use a much lower dose of the drug. Bioavailability: This is the proportion of an administered drug which enters the systemic circulation and have an active effect. And it describes the concentration of the drug in systemic blood in relation to the amount of drug given. So intravenous is 100%. Because all of it gets straight into the bloodstream. Because you're injecting it straight into a vein. IMS 1 TBL 5: Drug Metabolism (2) Intramuscular, reasonably between 75 and 100% bioavailable. You can use it for reasonably large volumes and it leaks out / distributes slightly slower. Subcutaneous, for example, insulin. and thats somewhere again between 75 and 100% of the dose. Oral, for example, can be somewhere only about 5% of the dose. But it's a lot more convenient than stabbing yourself with a needle, so sometimes people are happier with that. Rectal use, we were saying as one of the rates of administration, it's more absorbed, somewhere between 30 and 100%. So it has less first pass metabolism than the oral route and is very useful if the patient is being sick so they can't swallow or if they're unconscious. And then inhalation: Somewhere between five and 100%. That has a very rapid onset. So nebulisers for example, and aerosol inhalers. Then transdermal, so skin patches are somewhere between 80 and 100% bioavailable. Usually very slow absorption. And, for example, nicotine patches can be for something like 24 hours. And we have the butran's patches, which can be for up to a week at a time, which is buprenorphine. So some of factors affecting drug metabolism. IMS 1 TBL 5: Drug Metabolism (2) The disease states, so liver or kidney disease will affect drug metabolism. The age: neonates don't have all their liver enzymes present up until about six months, so they are unable to process. For number three: co- -administration of drugs using the same metabolic pathway will affect the speed of metabolism. Hence why with lithium, if patients are taking lithium for bipolar disorder, they must not take ibuprofen because they are both metabolised by the kidneys. And smoking inhibits the metabolism of aminophylline for example, which is used to treat COPD. So in patients with very bad breathing problems, when they give up smoking, hopefully that they do, we actually need to monitor their dose of aminophylline and reduce it usually by 50% because of the reduction in the enzymes and as we said one time before, the genetics one: people of African origin are unable to metabolise ACE inhibitors properly although they can metabolise the ARBs because it's a slightly different pathway. And nutrition: the elderly have lower albumin levels, which will affect warfarin which is an example here. Their normal albumin levels are lower so normally when you see the range on their blood test results, they are always slightly low. And this is where we're just saying about enzyme induction that speeds it up or inhibition that slows it down. IMS 1 TBL 5: Drug Metabolism (2) And then going on to excretion. Where it's the process by which drugs and their metabolites are removed from the body. So it can be excreted in fluids, solids or gases. Urinary excretion is the usual route of elimination for low molecular weight drugs. It will be affected by glomerular filtration rate if it's going to go through the kidneys. So if the GFR, when you look at your blood results that you've sent away, there'll be an EGFR result and this will estimate the glomerular filtration rate. And if this is very low, so below 30, then you will need to adjust doses. And if it's extremely low, then you really need to consider a product that is excreted by different mechanisms. So the process of excretion is irreversible. And as I was saying, the GFR is the flow rate of filtered fluids through the kidneys, and it's basically an estimate of how well the kidneys are working. When you look on your blood test results, normal results should be between 90 and 120 mls per minute per 1.73 metres squared - that's looking at the body surface area. And we have monitoring requirements for certain drugs such as digoxin with the kidneys so that we can make sure that they are safe and are not going to reach toxic doses. Again, this is just to point that bit out. IMS 1 TBL 5: Drug Metabolism (2) We have the duration of action, and the minimum toxic concentration, and the minimum effective dose. So that therapeutic range there in between is what we want to keep and not let it go above into toxic levels, and we don't want it to drop too low because it's not going to work, but it will still have some side effects. And if it has a narrow therapeutic index so these ones (listed on slide) that have a very low therapeutic range. So the bigger arrow in the middle there, if that's very, small, these drugs such as phenytoin, carbamazepine, digoxin, lithium and theophylline, have to be monitored carefully. This lets us work out the plasma half life. The half life is the time required for the concentration of the drug in the blood to decrease by 50%. The half life will affect the frequency of administration. So drugs with short half lives are quickly eliminated, while longer half lives stay in the body longer. So as you can see, indapamide half life is somewhere around about 16 hours. So you can give it once a day. Furosemide we give it twice a day, usually morning and lunchtime, so that patients aren't waking up overnight to go for a wee and pass urine. One with a very long half life is amiodarone. It is on average 50 days. IMS 1 TBL 5: Drug Metabolism (2) And it is highly protein bound. So the ones that have a very long half life, you give them a loading dose, which is around two or three times the regular dose eventually, and then over the space of a week or two at a time, you reduce the dose. Similarly, things like warfarin have a loading dose at the beginning because it's going to take quite a while for it to get up to a therapeutic range. So you have a bigger dose right at the beginning and then you work it down from there. Half life gives you an idea of a steady state. So the first graph that you saw was for one drug administration, one dose. And when it's regularly given you want it to be between that minimum effective dose and the minimum toxic dose. So you want it to stay in the working range. And it will take somewhere around about five half lives to reach steady state - five doses and around about five half lives to wash out if you have finished with them. Amoxicillin - Its half life is about 60 minutes Hence why you've got to give it generally three times a day. Amiodarone, like we said, 58 days. So this one has a loading at the beginning to get it up to a steady state. IMS 1 TBL 5: Drug Metabolism (2) And then you have a long washout period when you come off of it. So quite a few factors that affect Half-Life. It can be the patient's age, their ethnicity, and their renal function. So age with kidney function actually reduces after about the age of 65-70. You tend to use the cockcroft gault equation, which actually includes the age anyway. Also, you have got less protein binding or less globulin available as well - albumin with extreme age. And you will have some drug specific interactions We discussed about drugs that inhibit liver enzymes and induce liver enzymes already. Therapeutic index - you don't desperately need to know this. It is just to have a vague awareness of how much the difference between the toxic dose and an effective dose is. So very narrow therapeutic index, like we said, with lithium or phenytoin, for example. It will be a much smaller number. This one (Drug A on the slide as an example) is 1000, so this one's has a very big therapeutic index. Some of the narrow therapeutic index drugs... we have been discussing phenytoin, carbamazepine for epilepsy, digoxin for heart failure, lithium for bipolar. Theophylline for asthma and COPD. IMS 1 TBL 5: Drug Metabolism (2) Then some of the antibiotics so vancomycin, gentamicin and teicoplanin. These all have very narrow therapeutic indexes. So all those three antibiotics tend to be given by infusion and are monitored very, very closely when the patient is in hospital. Very rarely will you ever see those given in the community. This graph is just showing you, again, the difference between the therapeutic effect and the toxic effect. Warfarin in this particular case. There is a measure called the international normalised ratio (INR), which is the difference between a normal person's clotting time and that patients. It's this ratio that you want somewhere around about 2 to 2.5. It's used for the prophylaxis for DVTs (deep vein thromboses) and pulmonary embolisms. There is a special number which is around about ten when the patient's actually has got a metal valve in their heart. But normally it's somewhere around about 2 to 3. So under dosing would lead to the patient clotting and this would kill them, and overdosing leads to bleeding. And with that, this can easily be reversed by giving them an injection of vitamin K. Thank you. That's the end of the second part. IMS 1 TBL 5: Drug Metabolism (2)