Pharmacokinetics Workbook PDF

Pharmacokinetics Lesson 1 The volume of distribution (Vd) describes the relationship between the Administered Jose of a drug and the Plasma concentration that results. It’s a theoretical measure of how a drug distributes throughout the body. Vd = Dose of drug...

Pharmacokinetics Lesson 1 The volume of distribution (Vd) describes the relationship between the Administered Jose of a drug and the Plasma concentration that results. It’s a theoretical measure of how a drug distributes throughout the body. Vd = Dose of drug desired Plasma concentration Theoretical measure of how a drug distributes in the body. Assumes: 1. drug distribution is instantaneously 1. It isn't subject to metabolism or elimination Concentration prior to equilibration is a measure of an amount of drug in a given volume. A drug is in its most concentrated form before we administer it. 70kg Total body water 42L Extracellular fluid 14L Intracellular 282 Plasma 4L Interstitial 10L A drug with a Vd that is exceeds total body water (> 0.6 L/kg or > 42 L) is assumed to be lipophilic It will require a higher dose to achieve a given plasma concentration. An example is Propofol A drug with a Vd that is less than total body water (< 0.6 L/kg or < 42 L) is assumed to be hydrophilic It will require a Lower dose to achieve a given plasma concentration. An example NMB The higher the Vd, the higher the loading dose that must be given to achieve its effect. desired plasma concentration IV bioavailability 4 Loading dose = Vd. Bioavailability oral-varys ©2023 APEX Anesthesia Review All rights reserved You may use this workbook for personal use only. Duplicating, reproducing, selling or distributing this content or any content from www.apexanesthesia.com is a violation of our terms of service and strictly prohibited. Pharmacokinetics Lesson 2 & 3 Clearance is the Volume of plasma that is cleared of drug per unit time. CL is directly proportional to: blood flow to the clearing organ, extraction ratio t dose CL is inversely proportional to: half-life & drug concentration in the central compartment To maintain a steady-state concentration in the plasma, the infusion rate dosing interval must equal the Rate of drug clearance by metabolism & elimination As a general rule, steady-state is achieved after 5 half-times. If a drug has a long half-life, you can achieve steady state faster by administering a loading dose The plasma concentration curve in a two-compartment model illustrates the Biphasic decrease of a drug's plasma concentration after a rapid IV bolus. The alpha phase represents distribution from the central compartment (the plasma) to the peripheral compartment (the tissues). The slope of line A is influenced by a drug’s volume of distribution As a general rule, the more lipophilic the drug, the larger the Vd, and the steeper the slope. The Beta phase represents elimination from the central compartment. A rate constant describes the speed at which a reaction occurs (or how fast a molecule moves between compartments). Most of the drugs we administer follow a 2 compartment model. ©2023 APEX Anesthesia Review All rights reserved You may use this workbook for personal use only. Duplicating, reproducing, selling or distributing this content or any content from www.apexanesthesia.com is a violation of our terms of service and strictly prohibited. Pharmacokinetics Lesson 4 Elimination half-life is the time it takes for 50% of the drug to be removed from the body after a rapid IV injection. Elimination half-time is the time it takes for 50% of the drug to be removed from the plasma during the elimination phase. Complete the elimination half-time table. Half-Time Amount of Drug Eliminated % Amount of Drug Remaining % 0 100% 0 1 50% 50% 2 75% 25% 3 87.5 12.5/ 4 93.75% 6.251. 5 96.875% 3.125% The concept of half-times is really only applicable to drugs that follow a one compartment model. The bottom line is that we cannot determine the offset of anesthetic drugs by half_times alone The concept of context sensitive half-time takes the duration of drug administration into account. It’s the time required for the plasma concentration to decline by 50% after the infusion is Stopped The "context" is time Label the context sensitive half-times of opioids. fentanyl Alfertani Sufentanil Remifesta nil ©2023 APEX Anesthesia Review All rights reserved You may use this workbook for personal use only. Duplicating, reproducing, selling or distributing this content or any content from www.apexanesthesia.com is a violation of our terms of service and strictly prohibited. Pharmacokinetics Lesson 5 Ionization describes the process where a molecule gains a positive or negative charge. This molecular change affects a molecule’s ability to pass through cell membranes If you put a weak acid or weak base in water, a fraction will ionize, and the remaining fraction will be non-ionized. Most drugs are weak acids or bases. A drug that's a weak acid will tonate a proton to water (pH = 7). A drug that's a weak base will recieve/accept a proton from water (pH = 7). Ionization is dependent on the pH of the solution ttle pka of the drug pKa is a constant property of a molecule (i.e., the pKa of lidocaine is always 7.9). pH is a Changable property of a solution (i.e., the pH of the blood changes according to the patient's physiology). A drug's pKa equals the pH where 50% of the drug is ionized & 50% is unionized In an acidic solution, weak bases are more ionized In a basic solution, weak bases are more unionized In an acidic solution, weak acids are more unionized In a basic solution, weak acids are more ionized Ionized Non-Ionized Solubility H2O lipid lipophobic Lipophilic hydrophilic hydrophobic Pharmacologic Effect ✗activity Active Hepatic Biotransformation less likely more likely Renal Elimination More likely less likely Diffusion: BBB 70 yes GI tract no yes Placenta 10 yes ©2023 APEX Anesthesia Review All rights reserved You may use this workbook for personal use only. Duplicating, reproducing, selling or distributing this content or any content from www.apexanesthesia.com is a violation of our terms of service and strictly prohibited.  Pharmacokinetics Lesson 6 In your own words, discuss the concept of ion-trapping as it relates to the mother and fetus. Maternal/ Fetal Ion trapping occurs when an unionized molecule passes from the relatively basic blood of the mother into the more acidic blood of the fetus. Once this occurs the molecule is more likely to be converted into its ionized form, preventing it from crossing the placenta & causing fetal accumulation. This also increases the concentration gradient causing ear more unionized molecule from crossing ©2023 APEX Anesthesia Review All rights reserved You may use this workbook for personal use only. Duplicating, reproducing, selling or distributing this content or any content from www.apexanesthesia.com is a violation of our terms of service and strictly prohibited.  Pharmacokinetics Lesson 7 The Liver synthesizes plasma proteins. These proteins are too large to pass through cell membranes, which explains why they’re confined inside the circulation A drug bound to a plasma protein cannot Bind to a receptor or be cleared by a clearing organ Only when the drug is released from the protein is it able to travel elsewhere in the body. Think of plasma proteins as an intravascular storage compartment for drugs, because a drug bound to a plasma protein cannot bind to a receptor. Only when a drug is released from the protein is it able to travel elsewhere in the body The key takeaway is that the extent of plasma protein binding affects the intensity of drug effect + the drugs duration of action Key Facts Cp Increased By: Cp Decreased By: Albumin -Most plentiful plasma Liver Disease ¼ protein Primary determinant of plasma renal disease oncotic pressure old age TV2 =3 weeks malnutrition nperigmaatirvillyy cbhiantrsgedacidic drugs also ∈ basic t neutral drugs pregnancy α1-Acid Glycoprotein Surgical stress neonates Binds t MI basic chronic pain pregnancy RA Drugs Advanced age Beta- globulin binds T ¼ ¼ basic Drugs ©2023 APEX Anesthesia Review All rights reserved You may use this workbook for personal use only. Duplicating, reproducing, selling or distributing this content or any content from www.apexanesthesia.com is a violation of our terms of service and strictly prohibited. Pharmacokinetics Lesson 7 For drugs highly bound to plasma protein, we must conceptualize the bound and the unbound fractions. Only the unbound fraction (free fraction) of a drug is available to cross lipid membranes where the drug can ultimately engage its receptor and exert its physiologic effect. How do you calculate percent change? positive results = increase New value-old value ✗ 100 negative = decrease old value Describe how decreased plasma protein affects plasma protein binding. It decreases protein binding site leading to increased serum concentrations which makes the rate of metabolism & excretion increase. it can also lead to increased potency Describe how competition for binding sites affects plasma protein binding. It can cause displacement of drugs. E a lower binding affinity into the serum or prevent them from having a spot to find in the first place. 10 clinically relevant interactions as a result Clinically, an increased unbound fraction looks like an increase in potency. The Vd is inversly related to the degree of plasma protein binding. Highly protein-bound drugs typically have a slower rate of metabolism and elimination. The risk of adverse effects is greatest when a drug has a narrow therapeutic index. Which other situations cause alternations in plasma protein binding? ©2023 APEX Anesthesia Review All rights reserved You may use this workbook for personal use only. Duplicating, reproducing, selling or distributing this content or any content from www.apexanesthesia.com is a violation of our terms of service and strictly prohibited.  Pharmacokinetics Lesson 8 For the majority of drugs, the rate of metabolism depends on two factors: The concentration of drug at the site of metabolism. This is influenced by blood flow to the site of metabolism The intrinsic rate of themetabolic process This is influenced by genetics, enzyme induction t enzyme inhibition Discuss the difference between zero and first order kinetics. concentration concentration cut decreases at in half/wit of time a consistent rate/unit time 56 25 125 etc can result from more trus 1 } 5 then capacity to metabolize (enzyme) less trug then capacity to metabolize if a first order enzymatic path over snt an become ∅order ©2023 APEX Anesthesia Review All rights reserved You may use this workbook for personal use only. Duplicating, reproducing, selling or distributing this content or any content from www.apexanesthesia.com is a violation of our terms of service and strictly prohibited. Pharmacokinetics Lesson 9 Metabolism (biotransformation) is the enzymatic process of altering a molecule’s chemical structure. The Liver is the primary metabolic organ (hepatic microsomal enzymes of the P450 system). Other sites of metabolism include plasma, kidneys, GI tract The purpose of metabolism is to change a lipophilic , pharmacologically active compound into a hydrophilic , pharmacologically inactive byproduct. Water-soluble byproducts are easier to eliminate from the body. Sometimes the body converts an inactive molecule into a pharmacologically active molecule. This is called a prodrug fos propofol is a prodrug that is metabolized by alkaline phosphates to its active metabolite - propofol. A phase one reaction prepares the molecule for a phase 2 reaction. Common examples include: Oxidation – removes electrons from a molecule Reduction – atts elections to a compound Hydrolysis – adds H2O to a compound to split it apart A phase two reaction conjugates in entogenous a highly polar, water-soluble substrate to the molecule. This inactivates the drug and readies it for elimination. Common substrates for conjugation reactions include glucuronic acid, glycine Sulfuric acid, acetic acid, or a methyl group A phase three reaction involves ATP dependent carrier proteins that transport a drug across a cell membrane. These proteins are present in the kidney, liver, and GI tract. Enterohepatic circulation: Some conjugated compounds are excreted in the bile , reactivated in the intestine, and then reabsorbed into the systemic circulation. Valium & warfarin are examples of drugs that undergo enterohepatic circulation. metabolism = modification, Conjugation & elim ©2023 APEX Anesthesia Review All rights reserved You may use this workbook for personal use only. Duplicating, reproducing, selling or distributing this content or any content from www.apexanesthesia.com is a violation of our terms of service and strictly prohibited. Pharmacokinetics Lesson 10 Hepatic clearance is the product of liver blood flow and hepatic extraction ratio The extraction ratio is a measure of how much drug is delivered to the clearing organ vs. how much drug is removed by that organ. ER = 1.0 means that 100% of the drug delivered to the clearing organ is removed. ER = 0.5 means that 50% of the drug delivered to the clearing organ is removed. For a drug with a high hepatic extraction ratio (> 0.7), clearance is dependent on Liver blood flow Hepatic blood flow greatly exceeds enzymatic activity , so alterations in hepatic enzyme activity has little effect. For a drug with a low hepatic extraction ratio (< 0.3), clearance is dependent on the ability of the liver to extract the trug from the blood The amount of enzyme present influences changes in the liver's intrinsic ability to remove the drug from the blood. List the ERs for commonly used drugs. High intermediate Low rent mitaz Rouronium Sufent Vecuronium ramifert valium methohexital Lorazepam Morphine methcture meperidine Heopental Ketamine propolito,burivicaine theophylline, phenytoin When administered orally, high extraction ratio drugs are subject to first pess metabolism This explains the difference between oral and IV dose regimens. ©2023 APEX Anesthesia Review All rights reserved You may use this workbook for personal use only. Duplicating, reproducing, selling or distributing this content or any content from www.apexanesthesia.com is a violation of our terms of service and strictly prohibited.  Pharmacokinetics Lesson 11 The 1450 system is the most important mechanism of drug biotransformation in the body. While there are over 20 different P450 enzymes, CYP3A4 is the most important cytochrome P450 enzyme, metabolizing nearly 50% of the drugs we administer. What is an enzyme inducer? List several examples. by stimulating Induces an increase in the activity of a specific enzyme production of additional enzyme + speeds up the metabolism of truss metabolized by that specific enzyme. Reduces +1/2 Phenytoin, etch, barbituates, rifampin, tobacco, carbamazepine What is an enzyme inhibitor? List several examples. It competes for the binding sites on an enzyme decreasing sites for clearing truss Increases 71/2 Grapefruit, cimetidine, one prazole, isoniazid, SSRIS, erythromycin Ketoconazole List several examples of CYP enzymes, their substrates, inducers, and inhibitors. substrates inducers inhibitors CYP3A4 opioids:Fent, Sufert, Alfert, methadone Grape fruit juice Benzos: Mitaz, valium Kittt cimetidine, Erythromyce Local Anesthetics: Lido, bupivilainepropivica.ie barbiturates Tamoxifen Azoles cgt.EE?TiIrrt SSRI CYP 206 Codeine Morphine Disulfiram Isoniazid oxy SSRI hydrocodone Quinidine CYP (A2 erythromycin caffiere Tobacco Cipro cannabis ETOH theophylline ©2023 APEX Anesthesia Review All rights reserved You may use this workbook for personal use only. Duplicating, reproducing, selling or distributing this content or any content from www.apexanesthesia.com is a violation of our terms of service and strictly prohibited.  Pharmacokinetics Lesson 12 Elimination of metabolic waste into the urine is a key function of the kidney. Renal clearance is determined by the glomerular filtration & organic union section transporters A drug’s fate is determined by its polarity and the pH of the glomerular fluid. Hydrophilic drugs will be excreted unchanged Lipophilic drugs must undergo biotransformation reactions to increase their water solubility before they can be excreted by the kidneys. Lipophilic drugs that have not undergone biotransformation will be reabsorbed into the peri tubular fluid by diffusion Discuss glomerular filtration. Drugs Unbourt from protein are filtered outby the glomerulus. Protein bound drugs are resistant to filtration by the glomerulus. Discuss organic anion and cation transporters. Transport proteins in the proximal renal tubules secrete organic acids + bases into the urine. Organic anion transporters (OA : Lasia,thiazide diuretics, + penicillin organic cation transporters: (OCT): Morphine, Demerol, dopamine Urine pH influences whether drugs are excreted in the urine or reabsorbed into the peritubular capillaries. Acidic urine favors reabsorption of acidic drugs and excretion of basic drugs. Basic urine favors reabsorption of Basic drugs and excretion of acidicdrugs. How can you manipulate the pH of the urine? Acid: Amonium chloride or cranberry juice Base: Natteo,, acetrolanite ©2023 APEX Anesthesia Review All rights reserved You may use this workbook for personal use only. Duplicating, reproducing, selling or distributing this content or any content from www.apexanesthesia.com is a violation of our terms of service and strictly prohibited. Pharmacokinetics Lesson 13 The plasma is an important site of drug metabolism, specifically hydrolysis , which uses Water to cleve an ester linkage What drugs are metabolized by pseudocholinesterase? Succing choline Mivacurium Ester locals Tetracaine procaine Chloro procaine cocaine (+ hepatic) What drugs are metabolized by non-specific esterases? Renifert Remimazolam Esmolol (RBC esterase s) Etonidate (hepatic) Atra curium (+ hofmann) Clevitipine What drugs are metabolized by alkaline phosphatase? Fospropofol What drugs are metabolized by Hofmann elimination? africarium + Us esterases cisatricurium ©2023 APEX Anesthesia Review All rights reserved You may use this workbook for personal use only. Duplicating, reproducing, selling or distributing this content or any content from www.apexanesthesia.com is a violation of our terms of service and strictly prohibited.