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Pharmacokinetics and Drug Metabolism
- 2. bsorption istribution Conc. of Drug etabolism C-max xcretion Area Under the Curve or Total Exposure to Drug ½ C-max 0 Half Life T-max T-½ (Half-life) More drug IN than out More drug OUT than in Time
- 5. 3 POINTS about ROUTE of administration 1. 2. 3. C-max, T-max and Area under the curve differs Clearance is same Half-life is same Clinical issues related to oral bioavailability 1. 2. 3. In renal failure, there is decreased absorption due to chelation with co-administered antacids. Concurrent administration of food increases the absorption of ziprasydon, but decreases that of levosulpiride. Buprenorphine has poor oral bioavailability due to hepatic first pass metabolism, but it has good sublingual bioavailability.
- 6. TISSUE RESERVOIRS Bound Free THERAPEUTIC SITE OF ACTION Bound Free UNWANTED SITE OF ACTION Bound Free BLOOD LIBERATION ABSORPTION DRUG DOSE CLEARANCE [FREE DRUG] EXCRETION Protein bound drug LIVER Kidney metabolites BIOTRANSFORMATION Bile
- 7. Distribution of psychotropics • Distribution issues are somewhat uncommon with psychotropic medications. Most psychotropics are protein bound. (Lithium is exception). • So hypo-proteinemias can cause increase in free drug and so might require reduction in dosage. • Serum Blood levels of drugs include both protein bound and free drug. So this can be misleading.
- 8. Example of Distribution Issue • 48 year old male with history of bipolar disorder was treated with sodium valproate 1250mg and Quetiapine 500mg • Sensation of tingling in arm for more than 20 minutes – Concern about a transient ischemic attack (TIA) given untreated hypertention (155/95) and family hx – Started on enalapril 5mg bid and aspirin 325mg/day • Within 3 days, onset of fatigue, terrible fatigue and sedation and incoordination – Presention is consistent with valproic acid toxicity – Valproic acid level is unchanged – 95ug/ml • Recommendation; d/c aspirin
- 9. Rationale • Divalproic acid tightly bound to plasma proteins • Aspirin is also tightly bound to proteins – Displace valproic acid – Only changed ratio of bound to unbound valproic acid – Total amount of divalproic acid unchanged • Discontinuing Aspirin solved the problem.
- 12. CYP 450 Enzymes Slightly Water soluble DRUGS, OTHER XENOBIOTICS Water Insoluble PHASE-I FUNCTIONALIZATION POLAR (OH) METABOLITE PHASE-II CONJUGATION Phase-III Transport Urinary excretion FAECES MW >300 Conjugated METABOLITE Highly water soluble MW<300
- 13. Portal Vein CELL MEMBRANE OF HEPATOCYTE -H -H MDR CYP-450 NUCLEUS • Oxidation • Hydroxylation • Hydrolysis • • • • Glucuronidation Methylation Sulphation Acetylation -OH BILE ducts Smooth ER CYP-450 enzymes on smooth ER PHASE - I GLYCOPROTEINS Hepatic Vein -OH -OH -OH -OH -OH -OH -OH -OH Conjugating enzymes in Cytoplasm PHASE - II CELL MEMBRANE OF HEPATOCYTE Transferring enzymes acting on cell membrane PHASE - III BILE ducts
- 14. Main Cytochrome P450 enzymes in Humans Only few of 50 enzymes are involved in the metabolism of 90% xenobiotics and drugs 14
- 15. FACTORS AFFECTING CYP450 (1) • Age (Young metabolize faster) • Sex (Males metabolize faster) • Habits (Smokers and Chronic Alcoholics metabolize faster) • Genetic Polymorphism – Fast and Slow metabolizers • Drugs (CYP inhibitors and CYP inducers) – Inhibition occurs immediately – Induction takes time and is lasting
- 16. METABOLISM AND CYP450 (2) • Almost all psychotropics are metabolized by CYP450 Enzyme system – Except Lithium, Lorazepam, Gabapentin etc • CYP450 have – Substrates (drugs metabolized by CYP enzymes) – Inhibitors (drugs that inhibit CYP enzymes) – Inducers (drugs that increase CYP enzymes)
- 17. METABOLISM AND CYP450 (3) • Substrates – Almost all psychotropics. Thus they are susceptible to activity of inhibitors and inducers • Inhibitors – Many drugs including many psychotropics • Examples: Fluvoxamine, Paroxetine, Clomipramine, CPZ, Bupropion, Duloxetine, Moclobemide, Grapefuit juice • They increase the toxicity of substrates, reduce activity of prodrugs like aspirin, tramadol, codeine • Inducers – Examples: Carbamazepine, Phenobarbitone, Modafinil, Phenytoin, St. John’s Wort, Tobacco, Chronic Alcoholism – They reduce effectiveness of substrates after some time.
- 18. METABOLISM BEGINS IN THE GUT • The metabolism of many drugs starts in the gut itself. • The gut cells contain CYP-450 as well as the efflux pumps of MDR and p-glycoproteins which render much of the drug inactive. • Grapefruit juice inhibits these enzymes leading to large amount of drugs to enter portal system. • The felodepine trials using grapefuit juice to mask the taste of alcohol
- 19. Case of near fatality with Verapamil A 42-year-old lady brought in emergency. Doctors had to insert a breathing tube, and then a pacemaker, to revive her. She was taking a Verapamil to help prevent the headaches. Toxic level of verapamil in blood ? Attempted suicide by taking overdose ??? H/o grapefruit juice with verapamil
- 20. The mysterious Case of Fluvoxamine • • • • 75-year-old lady on Fluvoxamine-150 since 2 years. Sudden palpitations while vacationing. Grapefruit juice was served everyday by daughter. Naringin and Bergamottin in grapefruit inhibit the gut (but not hepatic) CYP-450 enzymes which metabolize Fluvoxamine. • People who have mutant genes for 2D6 CYP-450 develop severe anxiety reactions when given SSRIs in usual dose as they lack efficient 2D6 CYP
- 21. Grapefruit is none of these Grapes, Oranges or Sweet Lime Inhibits CYP450 3A4, 2C19, 2D6 SAFE
- 22. Some other Metabolism Issues (1) • Valproate should be avoided in liver disease. • Olanzapine dose needs to be reduced in liver disease. • Injectable Olanzapine is rapidly sedating when given i.m. • Injected psychotropics have higher steadystate levels in blood!
- 23. Some Metabolism Issues (2) • Risperidone has high effectiveness despite first-pass metabolism. • Clozapine becomes hematotoxic when carbamazepine is added. • Clozapine and Olanzapine lose effectiveness in smokers. • Ziprasidon is not affected by smoking.
- 24. Some Metabolism Issues (3) • Carbamazepine reduces the effectiveness of many psychotropic substances. • Valproate raises lamotregine levels
- 25. Some Metabolism Issues (4) • Lorazepam, Oxazepam and Temazepam are safe in liver disease but not other benzos. • Tramadol can cause serious interaction with SSRIs like peroxetine, fluvoxamine and sertraline.
- 28. docvmt@gmail.com
- 38. Interesting Titbits • The ongoing evolutionary battle between plant and animal
- 40. KIDNEY DAMAGE STAGING BASED ON GLOMERULAR FILTRATION RATE Normal GFR is 100-130ml/min/1.72m2 • • • • • Stage-1 Stage-2 Stage-3 Stage-4 Stage-5 >90 60-89 30-59 15-29 <15 (or dialysis)
- 41. Dose Cp Speed of drug removal C x Vu Clearance = u Cp Vu GFR Cu
- 42. Calculating GFR using Clearance • Isotope scanning • 24-hour urine collection of creatinine eCcr = Urine Cr excretion/min S. Creatinine • Inulin clearance (not insulin) – It is more ideal than creatinine as it is neither absorbed nor secreted by renal tubules, so it reflects GFR • Using GFR calculators using S. Creatinine value – CG (Cockroft and Gault Equation) eCcr = (140-age) x Weight in Kg x (0.85 if female) 72 x S. Creatinine in mg% – MDRD (Modification of Diet in Renal Disease)
- 43. Factors affecting GFR eCcr = (140-age) x Weight in Kg x (0.85 if female) 72 x S. Creatinine in mg% • Age – GFR declines with age (note how the GFR becomes half in an 80 yr old compared to the 20 yr old according to CG formula) • Sex – Female have lower GFR (note how females are assumed to have 15% lower GFR in the CG formula) • Weight – Note the CG formula • Race – This is not part of CG formula, but other GFR formulas do take it into account
- 44. Zero order kinetics. Eliminates fixed amount of drug every unit time 1st order kinetics. Eliminates 50% drug every t-1/2
- 45. [ DRUG CONCENTRATION] Zero order elimination. Fixed amount decreases per unit time. For ex. 10g alcohol per hour The point at which kinetics of drug elimination changes from zero to 1st order First order kinetics. Fixed % (half, or 50%) of drug eliminated every t1/2 TIME
- 47. Renal vs Hepatic Clearance Renally Cleared • Lithium • Gabapentine • Pregabalin • Topiramate • Amisulpride • Duloxetin • Milnacipran • Venlafexine Non-Renally Cleared • Divalproex • Quetiapine • Carbamazepine • Lamotregine • Haloperidol • Aripiprazole • Moclobemide • Reboxetin • Tianeptine • Buspirone • Zaleplon • Zolpidem • Zopiclone (excreted by lungs!)
Editor's Notes
- Thank you very much Dr. Nilesh Shah for your kind words of introduction. I also thank Dr. Gupte for putting his trust in me and suggesting my name as the speaker of this CME. And I heartily congratulate our chairman Dr. Bhave for conceiving a very challenging topic for this CME – Prescribing dilemmas in special populations at the Indian Psychiatric Society’s west zonal annual conference in October 2013, at Goa. The number of available drugs has increased tremendously over past few decades. The ever increasing treatment options has made treatment more and more complex for the practicing psychiatrist. It is difficult to remain up-to-date with growing database of drug actions and interactions. Choosing the right drug and choosing a right dose is quite a challenge, particularly for patients with organ impairment. The ability to anticipate a further damage to an already damaged organ, anticipating other toxic drug effects, or effectively dealing with treatment resistance is expected from a practicing clinician. Unfortunately, practitioners often fall well short of this expectation, especially where organ compromised patients are concerned. Mistakes in this population are in fact quite common and cause considerable patient morbidity and mortality which is in fact iatrogenic. There is increasing evidence of avoidable complications and treatment failures on account of doctor’s folly for which the patient pays a heavy price both medically as well as financially. But despite this, drug-drug interactions are rarely in the minds of otherwise excellent clinicians. Two major varieties of drug interactions are pharmacodynamic and pharmacokinetic drug interactions. It is relatively easy and straightforward to understand the pharmacodynamicdrug-interactions – for example, synergistic anticholinergic activity of amitriptyline with benztropine can produce constipation, retention of urine, heat stroke and delirium. And pharmacodynamic drug interactions are usually intuitively straightforward if one has working knowledge of a drug’s mechanism of action. But knowing how a drug acts, that is, knowledge of pharmacodynamics rarely imparts knowledge of its pharmacokinetics. While compromised organs are particularly vulnerable to drug toxicity, they also alter the way in which drug is handled by the body, how drug is absorbed, distributed, metabolized and excreted by the body. Most of the dilemmas facing the clinician lie in pharmacokinetic domain which is what we are going to talk about next. In the second part of the talk, we will discuss the dilemmas in the context of the specific organs. So, let us begin the first part of the series, which has to do with basic pharmacokinetics.
- So let’s begin with the pharmacokinetic acronym ● ADME. This stands for ● Absorption, which is how the drug gets into the body. ● Distribution, which is where the drug goes to in the body. ● Metabolism, which is how the body chemically modifies the drug, and finally ● Excretion, which is how the body gets rid of the drug. These are the four elements we need to consider when talking about pharmacokinetics of a certain drug. First we are going to discuss some of the more boring but extremely important aspects of pharmacokinetics and pharmacology. So I begin by drawing a graph ● here on the y-axis, we have the concentration of drug within the body, ● and on the x-axis, we have time. If we give a drug to a person at time zero, then we will see the concentration of the drug go up, and then fall as the drug is removed from the body. ● And that’s what we see on this graph. So in looking at this graph, we can see that ● in this section, the drug enters the body faster than it is being removed from it. Therefore the concentration of the drug in the body increases. Then after the peak of this graph ● The drug is removed faster from the body than it is entering. So the concentration of the drug in the body starts decreasing. This point ● at the top of the graph is important because it is the highest concentration of the drug in the body. Therefore we call this the maximum concentration or C-max. This is important because knowing the maximum concentration can help predict the therapeutic benefit and also the likelihood of side effects. The time at which the maximum concentration occurs, is called T-max. ● Now a slightly more confusing concept is the half-life of the drug. The half-life is by definition, the time it takes to remove half of the current concentration of the drug from the body. So let’s consider the half-life on this graph. If we begin at C-max, we want to see how much time it takes for the concentration of the drug to become half ● So here is the half C-max line. And therefore, ● The half-life, is often denoted t½● So just to summarize, ● the time it takes for the drug to drop to half of its current level, is the half-life. On this graph, this is the time between t-max and where I have drawn t ½ . Knowledge of half-life helps in predicting dosing schedules. Time needed for almost complete elimination of a single dose is 4 to 5 half-lives. But instead of a single dose, if the doses are repeated, a steady state is reached after 4 to 5 half-lives, instead of complete elimination. The last thing to look at in this slide ● is the area under the curve. And this is shown by the shading under the graph. ●This represents the total exposure to the drug that the body receives from the systemic circulation. This is a function of dose absorption, distribution and elimination. And that completes the basic introduction to pharmacokinetics.
- Next we shall start with Absorption. While looking at absorption we will only consider routes of drug administration in this CME.
- ● Let me begin by showing a very simplified body plan. And this body plan follows the flow of blood from the digestive system to the systemic arterial circulation. ● The blood flows from gut, via portal veins to ●liver sinusoids to hepatic veins and● via inferior vena cava to the● right side of the heart via pulmonary arteries to● lungs. Via pulmonary veins to● left side of the heart, then out through the aorta and into ●systemic circulation. What we are going to do is place drugs into different parts of the system and measure their concentration in the arterial circulation over a period of time. So let’s draw a set of axes.● On the Y-axis we have blood concentration of the drug and on X-axis we have time. We begin with the three most common routes of drug administration, oral ● intravenous● and finally inhalational ●. Let us examine the oral route first. ● Orally ingested drugs move in the blood in portal veins from gut to liver sinusoids to hepatic veins to right side of the heart to lungs to left side of the heart eventually into the systemic circulation. This takes quite some time. So what we get is the blue curve ● which means a slow rise in blood concentration, and then a fall as the drug gets absorbed into the tissues and is eliminated through metabolism and excretion. Note that the C-max is quite low and T-max is quite large. ● We will now contrast that with intravenous administration. As soon as we give the same dose intravenously, this drug does not undergo the first-pass metabolism of liver.● In intravenous or IV administration, the drug does not have to make such a long journey to reach the arterial circulation. From the vein it quickly reaches the right side of the heart, and then to the lungs, back to heart on its left side and finally into the arteries feeding systemic circulation. This results in the curve which shows a quicker rise of the drug concentration. ● Note that the C-max is larger and T-max is smaller ● even though the dose was the same as oral drug. This is because, IV is a more direct route of administration than orally. Now contrast both of these with the inhalational route. ● We use the same dose as the oral and intravenous routes, but this time we are giving this as an inhaled form. Many anaesthetics and nebilizers are actually given this way. The drug now only has to go to the heart and then straight into the arterial circulation. This means that the concentration of the drug shoots up extremely quickly, as depicted by the red curve.● So a much larger C-max and a very small T-max compared to prior two routes of administration. ● Remember that in all these three examples, the dose of the drug was identical, only the route of administration was different. ● So you can see how different routes may cause a totally different C-max and T-max . This is important when considering the applications for certain drugs. For instance, if you need to sedate the patient very quickly, then IV antipsychotic will get into the system much quicker than oral one. Conversely, a drug which has toxic effects associated with the high Cmax of intravenous route will be safe at the same dose if given orally.
- As far as routes of administration is concerned; I have three more points to make. ● Firstly, the AUC for IV route is by definition 100%. The AUC oral is less for the same dose due to absorption, gut-metabolism and first-pass liver metabolism. Bio-availability is defined as fraction of administered dose that reaches systemic circulation. Thus it is the AUC (oral) divided by AUC (iv) in case of orally administered drug. ●Secondly, complete clearance of drug usually takes the same time, regardless of route of administration or even the dose of drug. I said usually because most drugs follow the first order kinetics of elimination. We will examine this in detail later. Basically this implies the almost complete elimination of single dose of drug in 4-5 half life cycles. ●Thirdly, it’s important to know that the half-life of the drug remains the same regardless of the route of administration. This is because half-life is the property of how the drug is eliminated by the body, not how it is administered. So it will take the same amount of time for the drug to fall to half of its concentration in blood, no matter what was its C-max which depends on the route of administration and the dose administered. ● Now here are a few practical examples related to drug absorption. ● In renal failure, there is decreased absorption due to chelation with co-administered antacids. ● Concurrent administration of food increases the absorption of ziprasydon, but decreases that of levosulpiride. ● Buprenorphine has poor oral bioavailability due to hepatic first pass metabolism, but it has good sublingual bioavailability.
- ● Now we will briefly discuss distribution of drug in various parts of the body. ● Depending on how the drug is administered ● the drug is either absorbed or released ● in to the blood stream as ● free drug. Immediately the drug gets bound to plasma proteins so that the free drug that is available for therapeutic effect is decreased. ● If the drug is ingested orally, the free drug is not available for therapeutic action yet as it undergoes the first-pass-metabolism in liver. Thus both protein binding and first pass effect of liver effective reduce the amount of free drug now available for action. ● The action of free drug occurs both on target organs as well as ● on tissues where it produces unwanted effects. But if the drug has been liberated into blood stream directly, the first pass effect does not take place and relatively more amount of free drug is available for acting on target tissues – both desirable as well as undesirable. The first-pass effect in liver decreases the amount of drug before entering into systemic circulation, both by way of direct elimination into bile via MDR cell membrane proteins, and via elimination of products of biotransformation in liver being released into blood as well as bile as metabolites, so that they could be excreted via gut and the kidneys. The free drug, after first pass effect, passes into other tissues like muscle and fat where it is stored as reservoir. This is called redistribution. ● When drug has bypassed the first pass effect, more drug gets stored in these tissue reservoirs, from which the free drug is released into blood. ● The dotted line shows how liver eliminates directly through bile without sending the drug or its metabolites into blood. But through the hepatobiliary excretory pathway. Now we will see some clinical issues related to distribution.
- ● Distribution issues are uncommon with psychotropic medications. Most psychotropics are protein bound. (Lithium is exception).● So hypo-proteinemias can cause increase in free drug and so might require reduction in dosage.● Serum Blood levels of drugs include both protein bound and free drug. So this can be misleading. Let us take an example :
- ● A 48 year old man with history of bipolar disorder was treated with sodium valproate 1250mg and Quetiapine 500mg.● He reported tingling in lower arm for more than 20 minutes to his physician. ● The physician suspected Transient Ischaemic Attack as he knew the patient had untreated hypertension and a family history of stroke. ● So the physician started an antihypertensive and aspirin.● Within 3 days the patient had signs and symptoms of valproate toxicity although his valproic acid level in the blood was within normal limits.● The physician recommended discontinuation of aspirin, which led to relief from symptoms of valproate toxicity. What was the rationale of his decision?
- ● Sodium valproate is tightly bound to plasma proteins and ● Aspirin is also tightly bound to plasma proteins● Aspirin competitively displaced valproic acid from the proteins releasing it as free drug.● As this only changed the ratio of protein bound to free valproic acid ● the blood level of valproate remained unchanged.● Thus discontinuing Aspirin solved the problem.
- Now we are going to talk about drug metabolism.
- Drug metabolism often takes place in the liver, but metabolism can also take place elsewhere, such as in the lungs, intestines or the kidneys.The fact that most drugs get metabolized by liver is very important for pharmacokinetics. Because drugs given orally may be metabolized by the liver BEFORE they reach the systemic circulation. This phenomenon is known as first pass metabolism. Sometimes, first pass metabolism is so dramatic that it necessitates giving a drug intravenously as giving it orally would lead to significantly less active drug in the systemic circulation. Morphine is an example of this which is why it is so often given intravenously, rather than orally. However, today I am going to talk about the biochemistry of drug metabolism, in particular, the actions of the cytochrome P450 enzymes.
- All drugs are xenobiotics. Xeno means foreign substance found in a living body. The metabolism of drugs is part of body’s defense mechanism against toxic xenobiotics. Most psychotropics are fat soluble or water insoluble, and this is understandable as they must be lipid soluble in order to cross the blood brain barrier. ● Psychotropics are those xenobiotics which are water insoluble and become targets of Cytochrome P450 enzyme systems that are present in the liver cell attached to the smooth endoplasmic reticulum. The main aim of CYP-450 enzyme systems in the liver is to convert these insoluble xenobiotics to water soluble metabolites so that they could be excreted out of the body through the kidneys. CYP450 enzymes do this by adding a polar group –OH through a variety of processes called phase-I metabolism called FUNCTIONALIZATION. The addition of polar functional group to the drug moiety makes the new metabolite water soluble. Anything that has polar groups becomes water soluble, because water itself is a polar molecule. But this hydroxylated metabolite resulting from phase-1 needs to be made even more water soluble if it needs to be filtered through the kidney glomeruli. ● This is done by conjugating the hydroxylated metabolite with other molecules with many more attached polar groups. This is called phase-2 metabolism, or conjugation. The now highly water soluble metabolite is secreted by hepatocytes into systemic circulation, from where they enter the kidneys to be excreted through urine. ● But there are molecules which are too large to be filtered by the glomeruli. The metabolites with molecular weights less than 300 are excreted renally, ● but the larger metabolites with molecular weights greater than 300 are passed into the biliary collecting tubules in the liver and are stored in gall bladder and eventually excreted in the faeces. The metabolites of psychotropics are excreted both through the hepatobiliary system as well as the kidneys depending on their size and chemical structure.
- Let us see how a liver cell, hepatocyte deals with a xenobiotic. ● Here is a xenobiotic, which in our case is say a drug, a psychotropic for example. It is usually a hydrophobic molecule with a hydrogen atom attached to it. And here is the hepatocyte. ● with its nucleus, cell membrane and ● The smooth endoplasmic reticulum. The smooth endoplasmic reticulum is a cell organelle which has many enzymes attached to it, including the cytochrome P-450. ● And here we see the drug entering the hepatocyte. Certain xenobiotics are first of all removed from the hepatocytes as soon as they enter it, through the MDR glycoproteins in the cell membrane. The MDR proteins directly exude the xenobiotic into the biliary canaliculi around the apex of the hepatocyte and get excreted through bile. If the drug escapes removal through MDR protein on cell membrane into the bile, it gets deeper inside the hepatocyte where ● it is now acted upon by the CYP-450 enzyme attached to the smooth ER. The CYP-450 is a set of several enzymes which act on the water insoluble drug and through Oxidation, Hydrolysis or Hydroxylation succeed in making the drug water soluble by oxidizing the hydrogen atom to a hydroxyl group. This makes the molecule polar, and therefore water soluble, as water is also a polar substance. ● This is called phase I metabolism ● Brought about by CYP-450 enzymes on the smooth ER of the hepatocyte. ● The somewhat soluble hydroxylated moiety now the target of Phase-II metabvolism which seeks to make it even more water soluble by adding many more polar groups to it. ● This is brought about by enzymes in the cytoplasm (not the CYP-450, which are attached to ER). These enzymes attach larger moieties through Glucuronidation, Methylation, sulphation or acetylation. The resultant metabolite is highly water soluble as it has many attached polar groups like –OH. ● Now phase III involves transferring of these metabolites out of the cell ● through Glycoproteins. There are 2 arrows going out of the cell. What do they mean? It only means that the larger molecules enter the bile ducts for excretion into feces and ● the smaller molecules enter the hepatic veins and then into systemic circulation and into kidneys for excretion of smaller molecules. The metabolism can therefore be affected by drugs which inhibit the phase –I enzymes, that is the cytochrome system. But now more and more is being discovered about the effect of drugs on MDR efflux, phase-2 and phase-3 mechanisms as well, which do not involve CYP-450.
- What are the factors that affect the cytochrome P450 enzyme system?●Young people metabolize drugs faster, and old people slower. As a result, the dose should be lower and more widely spaced in older people. ● Females metabolize slower while men metabolize faster. ● You must take into account habits like smoking or alcoholism as both of them make them fast metabolizers. Both smoking and chronic alcoholism induce the hepatic cytochrome enzyme systems. Thus, for example, smokers might need higher doses of medicines. ● Genetic Polymorphism: The genes encoding CYP-enzymes come in different varieties. Some genes make enzymes which are functioning well, while other variants make poor functioning enzymes. The gene mutants are found in more often in certain races and groups because of obvious reasons. They also run in families. So a family history of drug non-response or drug-toxicity could have genetic basis. ● Drugs (CYP inhibitors and CYP inducers) Inhibition occurs immediately, for example, a single glass of grapefruit juice can inhibit CYP-enzymes immediately and upto 24 hours. But the enzyme induction takes few weeks to develop, for example, the clinical effects of enzyme induction from carbamazepine, will not happen immediately, but after some time. So we must take this into account when understanding the effect of enzyme inducers and inhibitors.
- Now let us examine some more issues:● Almost all psychotropics are metabolized by CYP450 Enzyme system ● exceptLithium, Lorazepam, Gabapentin etc● Cytochrome enzymes, like other enzymes have ● Substrates, drugs that are metabolized by them● Inhibitors , which are those drugs that inhibit the activity of cytochrome enzymes and ● Inducers, which are those drugs and substances that increase the activity of these enzymes.
- ● Almost all psychotropics are metabolized by the cytochome P450 enzyme system. ● Thus almost all the psychotropics are substrates. But the bioavailability of these drugs can be drastically affected by inhibitors and inducers of the cytochrome enzymes.● Many drugs including many psychotropics inhibit the cytochrome enzymes. Such inhibitors cause the substrate blood levels to rise leading to their toxicity. ● Examples of inhibitors of cytochrome P 450 are drugs like Fluvoxamine, Paroxetine, Clomipramine, CPZ, Bupropion, Duloxetine, Moclobemide, and Grapefuit juice.● Although they raise the drug level of substrates, they reduce the effectiveness of pro-drugs like aspirin, tramadol and codeine as these pro-drugs depend on cytrochrome enzymes to convert these pro-drugs in to their active forms. The effect of enzyme inhibitors begin immediately.● Examples of inducers of cytochrome enzymes are Carbamazepine, Phenobarbitone, Phenytoin, Tobacco, Chronic Alcoholism, St. John’s Wort, and Modafinil.● Unlike the inhibitors, the induction effect is seen after few days to weeks because enzyme induction is caused by action on the genes which produce these cytochrome enzymes. Thus, while a glassfull of grapefruit juice causes inhibition immediately, carbamazepine’s effect of induction requires a couple of weeks to develop. So, addition of carbamazepine results in reduction of effectiveness of substrates not immediately, but after some time.
- ● The metabolism of many drugs starts in the gut itself. ● The gut cells contain not only CYP-450 enzyme systems but also Multi-drug-resistance and p-glycoproteins which metabolize and expel the drugs back into the GI tract, so that less amount of the drug reaches the portal circulation. ● Of the many drugs and substances that inhibit the intestinal cytochrome enzymes is grapefuit juice. Many drugs are substrates to intestinal cytochrome enzymes and their blood level rise if they are taken along with grapefruit juice. ●This effect of grapefruit juice was discovered accidentally while studying the effect of alcohol on the antihypertensive drug felodepine. In order to double blind the study, felodepine plus alcohol was compared with felodepine without alcohol and grapefruit juice was used to mask the taste of alcohol. It was found that the felodepine levels in the blood rose five times those of previous studies in which grapefruit was not used. Let us look at some important clinical implications of this.
- Case of near fatality with verapamil.● A 42-year-old lady was barely responding when her husband brought her to the emergency room. Her heart rate was slowing, and her blood pressure was falling. ● Doctors had to insert a breathing tube, and then a pacemaker, to revive her. ● They were mystified: The patient’s husband said she suffered from migraines and was taking a blood pressure drug called verapamil to help prevent the headaches. ● But blood tests showed she had an alarming amount of the drug in her system, five times the safe level. ● Did she overdose? Was she trying to commit suicide? It was only after she recovered that doctors were able to piece the story together.● “The culprit was grapefruit juice,” said her nephrologist.“The patient didn’t overdose on medication. She overdosed on grapefruit juice. The previous week, she had been subsisting mainly on grapefruit juice. Then she took verapamil, one of dozens of drugs whose potency is dramatically increased if taken with grapefruit. In her case, the interaction was life-threatening.
- The mysterious case of fluvoxamine:● A 75-year-old lady with depression was fine with Fluvoxamine 150 mg since 2 years.● She developed palpitations when she visited her daughter on a vacation.The palpitations disappeared when she returned home.● It was revealed that her daughter was serving her grapefruit juice every morning during the stay.● Grapefruit juice contains naringin and bergamottin which inhibit the gut, but not hepatic, cytochrome P 450 enzymes which metabolize Fluvoxamine.● I am sure you have seen some people who develop severe anxiety reactions when given SSRIs in usual dose. These people lack an efficient gut cytochrome P 450 enzyme called 2D6 because they do not have the healthy gene which codes for this enzyme in the body.
- But remember, grapefruit is not the same as grapes. ● Grapes do not inhibit cytochrome enzymes of the gut. Nor is it narangi (Oranges) or Mausambi (sweet lime) that we so often see in India. So oranges, grapes and sweet lime are safe.
- Now let us look at some issues of metabolism:● Valproate is metabolized by liver apart from being hepato-toxic. An impaired liver causes raised valproate levels, increasing its hepato-toxic potential.● Olanzapine undergoes significant first pass metabolism. 40% of it is removed in first pass. So use very low dose in liver disorder where first pass is impaired. ● Injectable Olanzapine bypasses the liver at first pass. So it is rapidly sedating when given i.m.● Injected psychotropicsare escape first pass and so much larger amounts get stored in tissues and therefore have higher steady-state levels in blood!
- ● Risperidone too undergoes significant first pass effect. But as its 9-OH metabolite is equally effective, so the bioavailability is almost 100%.● Clozapine has a hematotoxic metabolite called nor-Clozapin. So cytochrome inducers inducers like smoking and carbamazepine can increase the chances of hematotoxicity associated with clozapin.● Both clozapine and Olanzapine are metabolized by cytochrome 1A2, which gets induced by smoking. Thus smoking reduces the efficacy of both these drugs. ● Unlike clozapine and olanzapine, Ziprasidon is not metabolized by 1A2 cytochrome which is induced by smoking. So it’s bioavailability is not affected by smoking.
- ● Carbamazepine induces CYP450 enzymes thus it reduces the effectiveness of many psychotropic substances. In contrast, oxcarbazepine is a weak inducer and so is not as hazardous as carbamazepine.● Lamotregine is not metabolized by phase-1 metabolism involving cytochrome. But its metabolism is by conjugation, which is phase-2 metabolism in liver. Co-administration with valproate doubles the lamotregine concentration in blood because valproate inhibits phase-2 conjugation metabolism of lemotregine. So this combination can prove fatal.
- ● Unlike other benzos,Lorazepam, Oxazepam and Temazepam are not metabolized by the cytochrome enzymes orphase-1 metabolism, but through phase-2 metabolism called conjugation. So they are not easily affected by cytochrome inhibitors or liver disease where cytochrome enzymes are affected.● Tramadol is an analgesic, but is also an SNRI. It is metabolized by 2D6 . Therefore combination with SSRI can lead to serotonin syndrome because of both both pharmacokinetic and pharmacodynamic reasons. SSRI inhibit 2D6 inhibition which raises the blood levels of Tramadol and tramadol being an SNRI synergizes with the SSRI property of SSRI causing seroterngic syndrome.● Breast feeding mother given codeine. She was an extensive metabolizer of 2D6 which converts codeine to morphine. This killed the baby.
- This is a useful website.
- The web site has a nice table of drugs divided into substrates, inhibitors and inducers of cytochrome p-450. Itcontinuously updates the latest information collected by research into the pharmacokinetics of drugs. It is highly recommended to check this website for reaching smart decisions about which drugs to combine in which patients. I have designed a software which is coming next.
- This software is an excel worksheet available to anyone on request.You can select any drug of interest and a list of enzymes that metabolize this drug pops up.You can then select these enzymes in a query box which will then tell you the inhibitors of these enzymes and inducers of these enzymes. You can then know which drugs can interact with the primary drug and cause its activity to go down through cytochrome induction or make it toxic by inhibiting cytochrome. You can write to my email docvmt@gmail.com and I will send you a copy free of cost.
- Let’s take the example of commonly used antihypertensive drug Clonidine. Type it at the top of yellow column.
- Now let’s see what is the enzyme which metabolizes Clonidine and what are this enzyme’s inhibitors and inducers.
- We see that the drug clonidine is metabolized by cytochrome p 450 enzyme called 2D6.
- The table automatically lists the inhibitors of enzyme 2D6 that can interact with clonidine and cause its toxicity.
- And the table also automatically shows the enzyme inducers, which are dexametazone and rifampin in this case.
- So, as the table shows, inhibitors of enzyme 2D6, for example, citalopram, clomipramine, escitalopram, fluoxteine, moclobemide,, ranitidine, sertraline, bupropion, paroxetine, duloxetine and grapefruit juice can cause toxicity of clonidine. So a person previously tolerating clonidine will develop clonidine toxicity if co-administered these drugs.
- Similarly, take the case of alcohol, also known as ethanol.
- This table shows that alcohol is metabolized by enzyme 2E1 and a person will develop toxicity symptoms with alcohol if coadmistered with dislufiram or grapefuit juice. The table also shows that alcohol induces its own metabolism and isoniazid also induces the enzyme. So a person over a period of time will be able to tolerate alcohol or will tend to drink more alcohol when co-administered with isoniazid.
- Similarly, this table of Clozapine shows that the drug loses its effectiveness if enzyme inducers like insulin are needed. Also, smokers are likely to be drug resistant to clozapine.Ziprasidone is one antipsychotic which is not affected by smokers as it is one of those antipsychotics which are not metabolized by enzymes that are induced by smoking. On the other hand, fluvoxamine and grapefruit juice can cause toxicity of clozapine.Thus we see that awareness of drug-interactions with cytochorme p-450 enzyme system is critical to understanding drug toxicity and resistance.
- Now some interesting titbits about cytochrome enzyme system.● which is actually the story of ongoing evolutionary battle between plant and animal.● Initially there was only plant life on earth. Around 400 million years ago, ● animals moved from oceans to land and started eating the plants. As a result, the plants developed toxic alkaloids to kill animals who ate them. The animals then developed an enzyme system to inactivate the alkaloids they ate in a way that alkaloids were inactivated before they reached systemic circulation. This was done by evolving the cytochrome systems in the gut as well as the liver. There are thousands of cytochrome enzymes in nature. The massive hetereogeneity of these enzymesis therefore thought to reflect the complex ongoing battle between plants and animals. Plants develop new toxic alkaloids to limit their consumption by animals - the animals develop new cytochrome enzymes to metabolise the plant toxins, and so it goes. It appears that the number of cytochrome genes exploded at about the time when organisms moved from the oceans to dry land - around 400 million years ago!I wondered why cytochrome P 450 enzymes are called so? Initially I guessed there might be 450 enzymes! Actually there are only around 50 cytochrome enzymes in human beings. Why cytochrome P 450? There's a story attached to this. Initially, when researchers realised how important cytochromes were in metabolism, they needed a way of identifying them unequivocally. We know that most cytochrome is anchored to membranes of the microsomal portion of the cell. If the solution of crushed cells absorbs light at a wavelength of 450nm compared it must contain cytochrome. Thus cytochrome P-450 stands for cyto – meaning cell, chrome means colour as the large cytochrome molecule has iron at its center, Pigment means the one which absorbs the light of wave length 450 angstroms.
- Now we will discuss excretion of drugs. Excretion is defined as an irreversible removal of drugs from the body. ●This is called clearance.There are many mechanisms by which the free drug and its metabolites are eliminated from the body – ● through urine,faeces, exhaled air, saliva, sweat and gastro-intestinal juices. Remember, the elimination of unabsorbed drug through faeces is actually not clearance as the drug has never “entered” the body. Also, the process of redistribution which removes the free drug from the blood into other tissue reservoirs, is actually not an elimination, and thus cannot be called clearance. Formost of drugs however, it is the renal and hepato-biliary clearance which are most important. We have already seen how liver excretes the drug or the drug metabolite into the bile, which in turn gets excreted with the faeces, and into the kidneys as water soluble metabolites which are expelled in urine.
- The clearance from kidneys depends on the blood flow to the kidneys and eventually the glomerular filtration rate. Indeed, GFR is the biological marker of kidney function. ●Normally kidneys filter 100-125 ml of blood every minute but this is diminished in renal impairment. The staging of renal impairment is based on reduction in glomerulas filtration rate.● Stage 1 is a renal disease without GFR impairment, so that GFR is greater than 90.● Stages 2,3,4 and 5 represent increasing degrees of impairment of GFR. If the patient is on dialysis, he is considered to be in stage 5.Now let us examine how the kidneys clear drugs.
- A drug in blood enters the nephron of the kidney. Once the drug is inside the nephron, it flows through the nephron, into the collecting ducts, and ultimately out of the body in urine. So we can define some values here. ● First of all, there is a certain concentration of the drug in plasma. We denote this Cp, concentration in plasma. ● Secondly, there will be a certain concentration of drug in the urine. We denote this Cu, concentration in urine. ● Finally, there will be a certain rate at which urine is being produced. We denote this by Vu, velocity of urine. From these values, we can determine the clearance of the drug. ● Clearance of drug is given by formula - Clearance = ● the rate of excretion of drug in urine ● which is the product of concentration of the drug in urine, and the rate at which urine is being produced, ● divided by ● the concentration of drug in plasma. This equation asks, “How much plasma contains the amount of drug being cleared at this time. ●The speed with which drug is being excreted is the top part of the equation. When the bottom part of equation is factored in, ● it will give us the volume of plasma containing that amount of drug being excreted per unit time. Another way of looking at clearance is, ● if there is certain amount of drug in the plasma, ●how quickly can I get rid of it. ●The clearance answers this question for us. Different things can happen to the drugs as they pass through the nephron. If they are reabsorbed, then the clearance will decrease. Conversely if the drug is secreted actively into the nephron, this will increase the concentration of the drug in urine, and thus also the clearance of that drug. It is a decrease in renal clearance of not only creatinine but renal clearance of any substancereflects the GFR. As creatinine is also secreted by the tubules in urine, creatinine clearance exceeds GFR. Substances which are neither absorbed nor secreted in the renal tubules more correctly reflect the GFR. For example inulin. But still creatinine is used to measure GFR as it does not require administration of any drug to measure renal clearance.
- In case of kidneys, only GFR is important. But it cannot be measured directly except ● through radio-isotope scanning. Indirect measures of GFR study the clearance function of the kidneys. Kidneys clear the blood of drugs and their metabolites, as well as natural by prodcuts like creatinine. Creatinine is exclusively eliminated renally and therefore creatinine clearance is a good indicator of renal clearance. ● 24 hour urine is collected and amount of creatinine is measured. Creatinineclearance in 24 hours can easily be converted to creatinine clearance per minute. When this is devided by s. creatinine, we get creatinine clearance, which gives a good estimate of renal clearance or GFR. But as creatinine is secreted by the renal tubules in the nephron, the clearance of creatinine exceeds GFR.● So inulin clearance is ideal as it is neither reabsorbed nor secreted. However, as this process involves administration of inulin from outside, creatinine clearance is preferred.● But 24-hr urine collection to measure creatinine amount excreted in 24 hours is also cumbersome. So generallyclinicans use GFR calculators which only need s.creatinine to find out creatinine clearance using formulas. ● There are many calculators, but the one most commonly used is the CockroftGault equation. The formula takes into account the age, weight and sex of the patient apart from the s.creatinine value. ● MDRD formula is another example of GFR calulator based on s.creatinine level.
- Let’s examine the factors affecting the Glomerular Filtration Rate● First is age. GFR declines steadily with age so that elderly always have a degree of renal impairment and therefore require a dose reduction for most drugs. ● If you see the CockroftGault formula, age is a part of the equation. According to this formula, an 80 year old person will have a GFR half that of a 20 year old man. When you subtract the age from 140, the 20 year old becomes 120, and the 80 year old becomes 40.● Second is Sex. ● A woman has 15% lower GFR than man and this is also indicated in the CG formula.● Thirdly, the GFR increases with weight, also indicated in the formula.● Finally, the GFR also depends on race, but this is not factored in the CG equation.
- As we saw earlier, the half-life of a drug a unit of time measure that it takes a specific drug to have it's blood concentration halved and this t½ remains constant for a drug in an individual. What this means is that 50% of the drug gets eliminated from the body every t½. ●This implies that the drug is eliminated faster initially because of higher concentration in blood. In the system I have drawn here, note that t-half is constant. This is called first order kinetics of elimination and this is shown in this graph. This means the drug is eliminated from body within same period (about 4-5 half lives), whatever be the route of administration of however large or small the dose may be. Now let’s change the situation a little. As we saw earlier, drugs often have to be metabolized prior to being sent to kidneys for excretion. A drug gets metabolized by an enzyme and then the metabolite gets excreted. In some situations, there is limited amount of enzyme and too much of the drug. The enzyme saturates. Meaning that it is all used up and is working at 100% of capacity. This means that if more drug is added to the body, it won’t change the rate of excretion, because there is no extra enzyme to process the extra drug. ● Accordingly, the curve is a almost a straight line initially instead of being concave like the one below it. Note that in this case, there is no half life. ● When a drug behaves like this we call it zero-order kinetics. Drugs following zero-order kinetics of elimination, do not get eliminated speedily● and within a fixed period, but take time which depends on the amount of drug taken. It gets eliminated slowly rather than exponentially because either the renal clearance is impaired or the hepatic clearance is impaired. Drugs with zero order kinetics are easily overdosed. As the rate of excretion does not increase with increase in dose. Alcohol is an example of a drug with zero order kinetics. Which is why no matter how much some one drinks his body will metabolize only about 10g of alcohol per hour. It is important to note that once the enzyme is no longer saturated, the elimination pattern follows first order kinetics. Aspirin and phenytoin are other examples of drugs that can acquire zero-order kinetics if given in larger doses without there being renal or liver impairment. But in face of renal or hepatic impairment, many drugs can acquire zero-order kinetics and can get fatally overdosed.
- 3 drugs easily get into zero-order kinetics even in absence of renal or heaptic impairment – alcohol, aspirin and phenytoin. Typically, poisons also follow zero-order kinetics of elimination. Most drugs follow first order kinetics as long as liver and kidney function normally but these drugs follow zero-order kinetics when the body is unable to clear the drug from body as happens in renal and liver diseases. In these cases, any drug can become easily overdosed and become toxic. In this graph ● we see how a drug which follows zero order kinetics of slow clearance initially, later on regains the fast first order kinetics when the blood concentration falls enough to stop overwhelming the body’s clearing mechanism. ● The point at which this change of order occurs is indicated.
- This chart shows the essential differences between the two orders of clearance kinetics. The first order kinetics is the physiologically normal way of metabolism and excretion of a substance. In this mode, a fixed percentage of the substance is cleared – technically, 50% of substance is cleared in a unit of time called t-half. In this, the clearance is faster initially as the concentration in blood is higher. In contrast, the zero-order kinetics suggests a drug kinetics in which the body’s limited mechanism of drug metabolism and elimination are overwhelmed and the substance elimination hits a bottleneck.
- This table lists psychotropic drugs according to the predominant mode of clearance. It is only necessary to remember the renally cleared drugs because most other psychotropics are cleared hepatically except Zopiclone, which is largely cleared through the lungs! And with this we end the first part of this talk about fundamentals of pharmacokinetics necessary for dealing with the prescribing dilemmas of the organ compromised patients. In the second part of the talk, we will examine the dilemmas pertaining to four organs – the liver, the kidneys, the brain and the heart.
- This ends the first part of the talk on Prescribing Dilemmas in the organ compromised patients and this part dealt with pharmacokinetic principles.
- In the next part, we will discuss the prescribing dilemmas in the context of individual organs.
- Hope to see you again for the 2nd part of the series. Thank you for your attention.