Drug Metabolism And Excretion (Pharmacology) PDF

DRUG METABOLISM AND EXCRETION Readings: Ch 8-10 in Pharmacology Revealed © Dr. E. Cates, Fall2021 1 LAST TIME, ON PHARMACOTHERAPY… • Distribution of drugs • Volume of distribution • Calculation of Volume of Distribution • Loading Dose • Calculation of Loading Dose • Drug administration & dosin...

DRUG METABOLISM AND EXCRETION Readings: Ch 8-10 in Pharmacology Revealed © Dr. E. Cates, Fall2021 1 LAST TIME, ON PHARMACOTHERAPY… • Distribution of drugs • Volume of distribution • Calculation of Volume of Distribution • Loading Dose • Calculation of Loading Dose • Drug administration & dosing • Continuous infusions • Discrete dosing • Today: • How drugs leave the body • Adverse drug reactions © Dr. E. Cates, Fall2021 12 DRUG CLEARANCE • Once a drug is taken into the body it is seen as a toxin • Needs to be removed • How is drug removed from the body? • Otherwise known as cleared from the plasma… • The process of elimination involves 3 major routes: 1. Hepatic metabolism 2. Elimination in bile 3. Elimination in urine © Dr. E. Cates, Fall2021 13 DRUG METABOLISM (LIVER) & ELIMINATION (KIDNEY) Elimination into the urine requires small or ionized or hydrophilic molecules: BUT: • Most drugs are not small molecules that are ionized at body pH • Most drugs are poorly ionized and lipophilic  this decreases renal excretion and facilitates renal tubular reabsorption • Many drugs are highly protein bound • Most drugs would have a long duration of action if termination of effects depended only on renal excretion Solution Drug Metabolism! © Dr. E. Cates, Fall2021 14 DRUG METABOLISM (LIVER) & ELIMINATION (KIDNEY) *The liver ultimately makes the drugs more water soluble so they can be more easily excreted in the bile or through the kidneys Drug Metabolism © Dr. E. Cates, Fall2021 15 DRUG METABOLISM • Most drugs are chemically changed in the body • Called metabolism or biotransformation • Main purpose of metabolism is to eliminate the drug • Not all drugs have to be metabolized to be excreted • E.g., 90 % of PenG is excreted in the urine unchanged, the other 10% leaves in the filtrate • Nitrous Oxide is not metabolized, but exhaled • Main site of metabolism is the liver • Kidneys and gut wall also metabolize drugs © Dr. E. Cates, Fall2021 16 DRUG METABOLISM – THE LIVER • The biochemical reactions of metabolism are carried out by enzymes • These enzymes are found in the microsomes (fragments of the endoplasmic reticulum) of hepatocytes • The liver is the most important organ in drug metabolism • Liver dysfunction will increase the life of many drugs in the body • E.g., acetaminophen (TYLENOL, antipyretic, analgesic) meperidine (DEMEROL, opioid analgesic) and alcohol will persist for a great length of time if there is hepatic disease because they are completely metabolized by liver © Dr. E. Cates, Fall2021 17 DRUG METABOLISM – THE LIVER • Most of the time, metabolism of drugs by the liver allows them to be excreted by the kidneys • Some of the output of the liver is removed in the bile (biliary elimination) • Biliary excretion is particularly important for materials that are lipophilic • Bile exits via the common bile duct to the small intestine at the duodenum • Enterohepatic cycling may occur • This means that metabolized drugs are reabsorbed from the GI tract • E.g., in bilirubin excretion, bilirubin diglucuronide (conjugated form) has the glucuronide residues removed in the small and large bowel and thus can be reabsorbed into the blood © Dr. E. Cates, Fall2021 18 DRUG METABOLISM – THE LIVER Biliary Excretion • Active transport over passive diffusion • Drug goes from: the liver → bile → intestinal tract → eliminated from the body in the feces Enterohepatic Recycling • Sometimes, instead of being eliminated in the feces, the drug is reabsorbed from the intestine • The portal circulation takes the drug back to the liver Image Sourced from: https://toxtutor.nlm.nih.gov/13-003.html © Dr. E. Cates, Fall2021 19 DRUG METABOLISM • Most metabolic products are usually less pharmacologically active • Some examples of exceptions: Carcinogenic metabolites: • • Benzene gets metabolized by liver, ring opens, causes leukemia Aflatoxin: fungal contaminated peanuts in tropics, metabolized by liver, causes tumors Toxic metabolites: e.g., acetaminophen • • © Dr. E. Cates, Fall2021 Metabolite is toxic but at low doses, it is detoxified by conjugation; at high doses of acetaminophen, toxic metabolite cannot be conjugated and remains toxic Alcohol increases enzyme that breaks down acetaminophen = don’t drink and take acetaminophen, even morning after… 20 DRUG METABOLISM PRODRUGS • Sometimes metabolism is taken into account when designing drugs • A PRODRUG is a drug given in an inactive form that is later metabolized into an active compound • Process called bioactivation • This can get drugs across normally impermeable membranes, and avoid substantial first pass metabolism • • E.g., nitrofurantoin: antibiotic for UTI, bacterial prodrug E.g., erythromycin: easily destroyed by acidic pH and irritates GI tract but add an ester, and it increases lipid solubility for better absorption; ester needs to be hydrolysed for antibacterial activity © Dr. E. Cates, Fall2021 21 PRODRUGS: CODEINE © B Wainman • CYP2D6 (a liver enzyme) carries out the conversion (it is called an 0-demethylation because a methyl group is snipped off of the oxygen of the codeine) • Some people carry a genetic variation for CYP2D6 that cause the enzyme to carry out this reaction to a greater extent – these people are called ultra-rapid metabolizers • If you are an ultra-rapid metabolizer of codeine, much more, possibly toxic amounts, of morphine will show up in the blood and milk; see Koren, et al., Lancet, vol 368 p. 704, Aug 2006 for a case where the baby of a ultra rapid metabolizer of codeine died from morphine overdose © Dr. E. Cates, Fall2021 22 PRODRUGS: VALACYCLOVIR © B Wainman • Valacyclovir (VALTREX) is a potent antiviral drug – useful against herpes simplex virus I and II • Valacyclovir is converted to the active antiviral acyclovir (ZOVIRAX) by removal of an ester group • This de-esterification in the gut wall and liver is important because valacyclovir is 5X more orally available than acyclovir © Dr. E. Cates, Fall2021 23 DRUG METABOLISM Drug metabolism is conceptualized in 2 phases: Phase I • Drugs are oxidized or hydrolyzed Phase II • Drugs are conjugated © Dr. E. Cates, Fall2021 24 PHASE I REACTIONS • Convert parent compound into more polar (charged; hydrophilic) metabolite • Adding or unmasking functional groups (-OH, -SH, NH2, -COOH) • Drugs are oxidized or hydrolyzed • These metabolites are often pharmacologically inactive • May be sufficiently polar (hydrophilic) to be excreted after Phase I © Dr. E. Cates, Fall2021 25 PHASE I REACTIONS: OXIDATION Oxidation • Loss of an electron/hydrogen • Gain of oxygen bonds acetic acid Mnemonic #1: Mnemonic #2: loss electrons oxidation OIL LEO oxidation is loss © Dr. E. Cates, Fall2021 26 PHASE I REACTIONS: OXIDATION Example: Oxidation of Ethanol • Oxidation occurs in the liver • In most people the ability to metabolize alcohol is dependent on the ADH level • Different in different people based on genetic make-up OH H H ethanol © Dr. E. Cates, Fall2021 H ADH H O O ALDH H H H H H acetaldehyde H H OH H acetic acid ADH = alcohol dehydrogenase ALDH = acetaldehyde dehydrogenase 27 PHASE I REACTIONS: HYDROLYSIS Hydrolysis • A chemical reaction in which the addition of a water molecule leads to the breakdown of the molecule • E.g., ester groups are broken down in this fashion • Enzymes = esterases • Procaine (NOVOCAIN) is broken down in this way © Dr. E. Cates, Fall2021 28 PHASE I REACTIONS: ENZYMES • The enzymes that carry out phase I reactions are called cytochromes (CYPs) • Greatest concentration in liver; also in gut, lungs and other tissues • At least 12 CYPs important for drug metabolism • Biological functions include conversion of testosterone to estrogen (CYP19 also called aromatase) • Many interact with drugs and food – can lead to drug interactions • Ketoconazole, grapefruit juice bind to and inhibits CYP3A4  inhibits metabolism of domperidone and many other drugs • Ciprofloxacin strong inhibitor or CYP1A2  inhibits metabolism of ondansetron © Dr. E. Cates, Fall2021 29 PHASE I REACTIONS: ENZYMES • Levels of CYPs vary across individuals and can result in hyper- or hyposensitivity to drugs • CYP2C19: for metabolism of certain anti-depressants, antiepileptics • Only 3% of Caucasians are deficient in CYP2C19 enzymes, but 25% of Asians deficient Various factors affect CYP activity: • Factors increasing level (and activity) of CYPs • Called enzyme induction = decreased drug effect: • Nutrition, alcohol, smoking, other drugs, pregnancy • Several days of phenobarbital use can increase a number of CYPs • Hyperforin (St. John’s wort) induces CYP3A4 • Factors decreasing level (and activity) of CYP enzymes • Increased drug effects • Pregnancy inhibits CYP1A1 (caffeine) and CYP2C19 © Dr. E. Cates, Fall2021 30 Remember: Purpose of Phase I • If the drug is now hydrophilic enough, can be excreted via the kidneys • If not, another step is needed Phase II © Dr. E. Cates, Fall2021 31 PHASE II REACTIONS • Conjugation with an endogenous substrate to increase solubility • Conjugation with glucuronide, sulfate, acetate, amino acids, other compounds • Carried out by enzymes called transferases • Generally, follow phase I reactions © Dr. E. Cates, Fall2021 32 PHASE II REACTIONS • Definition: coupling of a drug molecule to one or several molecules to yield greater water solubility A Biological Example • Glucuronidation is the most common conjugation reaction • Catalysed by glucuronyl transferase • Neonates  deficient in this conjugation system • Bilirubin (insoluble) is conjugated with two glucuronic acid molecules to make bilirubin diglucuronide (water soluble) © Dr. E. Cates, Fall2021 33 PHASE II REACTIONS: ELIMINATION OF BILIRUBIN 34 © Dr. E. Cates, Fall2021 Image sourced from: www.pinterest.com DRUG EXCRETION The Kidney • Most important organ in the elimination of drugs and drug metabolites • Any decrease in kidney function will vastly increase the life of many drugs in the body • The newborn kidney filters only 4-6% of cardiac output vs. 25% in adults • Adult levels of filtration are reached at 6 months • Drugs that rely on renal filtration will have extended t1/2 in newborns • Anuria will increase a drugs life by 25% • E.g., the t1/2 of gentamycin will go from 2h to 35-50h if the patient is anuric In pregnancy, the GFR is much higher. What do you think this does to the t1/2 of drugs? © Dr. E. Cates, Fall2021 35 DRUG EXCRETION Kidney Function • The kidney has three ways of interacting with drugs: 1. Glomerular Filtration • Molecules smaller than about 4nm leave the glomerulus and enter the filtrate – passive process • Drugs that are bound to albumin and other plasma proteins will not enter the filtrate • The amount of glomerular filtration and thus the clearance rate of many drugs varies with the volume of blood filtered © Dr. E. Cates, Fall2021 • E.g., in pregnancy, the GFR increases 40-65% because of increased blood volume. This leads to increases in drug excretion into urine 36 DRUG EXCRETION Kidney Function 2. Tubular Secretion • Moves solutes out of the peritubular capillaries and into the filtrate • Need an active transport mechanism (specific carrier proteins) to transport anions and another transport mechanism for cations • Since the carrier system can be saturated, can be used for therapeutic advantage • E.g., the penicillins all undergo extensive tubular secretion • The drug probenecid also uses the same carrier mechanism and can be given to inhibit the secretion of penicillin – blocks secretion and make penicillin levels stay higher longer © Dr. E. Cates, Fall2021 37 DRUG EXCRETION Kidney Function 3. Tubular Reabsorption • Normally passive process • Drug moves down concentration gradient back to the capillaries • Gets more concentrated as it moves forward towards distal tubule • So, if the drug is lipophilic, it can diffuse across into the circulation (down its concentration gradient) • Fluctuations in urine pH can keep the in tubules (ion trapping) © Dr. E. Cates, Fall2021 38 CLINICAL PHARMACOKINETICS • The movement of drugs in the body • The concentration of drug in the blood is directly related to its effects on the body • Predicting the amount of drug in blood requires you to know: • Dose of drug administered • Amount of drug that ends up in the blood • Clearance of the drug from the blood • Rate of elimination • Vast majority of drugs follow first-order kinetics (rate of clearance is proportional to drug concentration) • Three drugs follow linear, zero-order kinetics: ethanol, aspirin, and phenytoin © Dr. E. Cates, Fall2021 39 FIRST-ORDER DRUG KINETICS Distribution Phase Concentration of Drug (mg/L) Elimination or Clearance Phase 12 10 The distribution phase is very quick with IV drugs 8 During the clearance phase the amount of drug decreases very rapidly at first and then slows down 6 4 2 0 2 4 6 8 10 12 14 16 18 20 Time (min) IV drug injection © Dr. E. Cates, Fall2021 40 DRUG CLEARANCE AND ELIMINATION • Drug clearance = removing drug from systemic circulation • Expressed as volume of plasma cleared of drug (litres/hour) • Drug elimination = time taken for drug clearance • Expressed as drug’s half life (time taken for drug concentration to decrease by half) • Why do we look at volume of blood cleared per unit time?? • Because drugs are cleared in concentration-dependent fashion • The more drug in circulation, the more drug is cleared from circulation => First-order kinetics • The only constant part of drug clearance is the amount of plasma cleared of drug; • The amount of drug cleared constantly decreases © Dr. E. Cates, Fall2021 41 HALF-LIFE Distribution Phase Concentration of Drug (mg/L) Elimination Phase 12 The concentration at 3 min is 10 mg/L. The concentration at 6 min is 5 mg/L. Is the half-life 3 min since the concentration dropped 50% 3 minutes? 10 8 If 3 min is the half-life, when we go out a further 3 min the concentration should fall 50 % once again. It does- the concentration at 9 min is 2.5 mg/L (exactly half of what it was 3 min before) 6 4 2 0 2 4 6 8 10 12 14 16 18 20 Time (min) IV drug injection © Dr. E. Cates, Fall2021 42 HALF-LIFE • Half-life (t1/2) is the rate of change of a drug • In pharmacology this term refers to the time required by the body to reduce the concentration of a substance by half • E.g., the half-life of oxytocin (PITOCIN, uterine stimulant) is 16 min • Therefore, after 1 min to 6 min 50% of the drug is metabolized and can be given again • Knowledge of a drug’s half-life is ESSENTIAL to planning dose regimens © Dr. E. Cates, Fall2021 43 FIRST-ORDER KINETICS • In the previous example the first 3 min led to a decrease in drug from 10 mg/L to 5 mg/L while the 2nd 3 min only led to a decrease of drug to 2.5 mg/L  this means that the half-life is 3 min • The amount of drug metabolized in every time period is different but related to the total amount of drug in circulation • This is the essential feature of 1st order kinetics  the more drug there is the faster it is cleared; the only thing that is consistent is the time to decrease the drug concentration by half • This is because the processes which work to clear the drug work faster when there is more drug available  drug metabolism is proportional to drug dose = 1st order kinetics • First-order kinetics are by far the most common type of clearance pattern seen for drugs in the body © Dr. E. Cates, Fall2021 44 ZERO-ORDER DRUG KINETICS Concentration of Drug (mg/L) Distribution Phase 12 Metabolism Phase The concentration at 4 min is 11 mg/L. The concentration at 10 min is 5.5 mg/L. Is the halflife 6 min because the concentration has dropped 50% in 6 min? No, if we go a further 6 min, all the drug is gone so the half-life cannot be 6 min. In fact there is no half-life for this drug. 10 8 6 4 2 0 2 4 6 8 10 12 14 16 The drug is broken down at exactly the same rate every min so the excretion is not dependent on concentration. The change in concentration is very close to a 18 steady20 1 mg/L/min. Time (min) IV drug injection © Dr. E. Cates, Fall2021 45 ZERO-ORDER KINETICS • The amount of drug metabolized in every time period was the same and not related to the total amount of drug in circulation. • This is the essential feature of zero order kinetics  the amount of drug does not alter the rate of breakdown. There is not a half-life and the only thing that is consistent is rate of clearance. • Due to saturation kinetics: the processes for drug removal are saturated and cannot change; the processes which work to clear the drug are saturated and cannot work faster when there is more drug available • Zero-order kinetics are a much less common type of clearance pattern seen for drugs in the body but if you increase the amount of drug to a high enough degree to saturate the clearance system then saturation kinetics will begin to appear for any drug. • Drugs like alcohol are cleared from the body by zero order kinetics, that is why “one drink per hour” makes sense. Drinking more does not make you excrete the alcohol any faster, but you will certainly excrete the alcohol for longer. © Dr. E. Cates, Fall2021 46 ZERO-ORDER KINETICS Concentration of Drug (mg/L) Distribution Phase Elimination Phase 12 10 8 6 4 Zero-order kinetics become first order kinetics once the drug clearance pathways are no longer saturated. Normally drugs which show zero order kinetics are very slow to clear because of a greatly lengthened metabolism phase. 2 0 2 4 6 8 10 12 14 16 18 20 Time (min) IV drug injection © Dr. E. Cates, Fall2021 47