ChemistryAnes2024.pptx

Chemistry of Anesthesia Fall 2021 The Relationship Between Chemistry and Pharmacology Nearly all drugs and medicines are organic materials. Most drugs that CRNAs administer are compounds- chemicals containing atoms connected by chemical bonds The properties of drugs are determined by...

Chemistry of Anesthesia Fall 2021 The Relationship Between Chemistry and Pharmacology Nearly all drugs and medicines are organic materials. Most drugs that CRNAs administer are compounds- chemicals containing atoms connected by chemical bonds The properties of drugs are determined by atoms and chemical bonds Knowing what types of atoms make up a compound and the effect of certain atoms on the biological system enables the design of drugs that will have desired effects The Relationship Between Chemistry and Pharmacology A basic understanding of the following is necessary: Elements on Periodic Table essential to pharmacology and everyday life Types of bonds that are formed between atoms Affect physical properties Biological activity Functional groups & combinations Water solubility Nomenclature General routes of metabolism Functional Groups  Functional Groups Organic molecules have two parts: Carbon backbone that is relatively inert One or more functional groups A functional group is a set of atoms bonded together in a specific way Functional groups largely define the chemical and physical properties of the compound You can expect molecules with similar functional groups to have similar physical and chemical properties Chemists prepare new potential medications by synthesizing derivatives of known compounds by manipulating the functional groups, attempting to fine- tune their physiological properties Copyright © Springer Publishing Company, 5 LLC. All Rights© 2017 Springer Publishing Company, LLC.  Oxidation and Reduction Oxidation is the loss of electrons and reduction is the gain of electrons. Reduction: Number of bonds to oxygen decreases or the Key number of bonds to hydrogen increases, the species has undergone reduction. We live in an oxidizing environment because there is so much oxygen in the atmosphere Terms Oxidation: Oxidation may be manifest by an increase in ionic charge (e.g., Fe2+ → Fe3+)/ increasing the number of bonds to oxygen accompanies decreasing the number of bonds to hydrogen The oxidizing power of oxygen makes many oxidation reactions exothermic and thermodynamically favorable processes Oxidation represents a chemical pathway to extract the chemical potential energy stored in the carbon-hydrogen and carbon-carbon bonds in an organic molecule 7 © 2017 Springer Publishing Company, LLC.  Conjugate is a compound formed by the fusion of 2 or more chemical compounds together Hydrolysis: breaking apart a molecule Key or bond by the addition of water Terms Hydrophilic- water loving- property or part of a molecule that is drawn to water and other polar molecules Hydrophobic- water fearing- molecule or functional group to repel water and other polar molecules 8 © 2017 Springer Publishing Company, LLC.  Lipophilic- lipid loving- molecule or functional group that is drawn to hydrocarbons Key Terms and other molecules that are not water soluble 9 © 2017 Springer Publishing Company, LLC. Types of Functional Groups 10 © 2017 Springer Publishing Company, LLC.  Amines are derivatives of Amines ammonia (NH3 ) and have (-NH2, - the general formula NR3. NHR, - Only one or two of the R NRR, groups may be hydrogen. +NRR’R” All amines have a lone pair ) of electrons on the nitrogen. 11 © 2017 Springer Publishing Company, LLC.  Functional groups derived from ammonia (NH3) Nitrogen analogs of alcohols Can form hydrogen bonds and tend to be more Amines soluble in water than many other functional classes A large number of medications are amines Probably the most important chemical reaction of amines is the basicity of amines Most have a noticeable base strength and will accept a proton from a strong acid to form its conjugate acid (an ammonium salt) 12 © 2017 Springer Publishing Company, LLC.  Alcohols have the general formula ROH, where R represents any alkyl group. The hydroxyl group (-OH) of Alcohols alcohols is highly polar and easily forms hydrogen bonds with other polar molecules. The polarity of the hydroxyl group allows alcohols to dissolve many other polar molecules. 13 © 2017 Springer Publishing Company, LLC.  Metabolism: Alcohol is oxidized to acetaldehyde then to acetate finally to CO2 Alcohol Ethanol also metabolized the same way Disulfiram(Antabuse) inhibits oxidation reation Results in extreme nausea © 2017 Springer Publishing Company, LLC. 14  Conjugation-turning substances into a hydrophilic state in the Alcohol body Metabolis m Alcohol to glucuronic acid or sulfuric acid Common alcohol metabolites © 2017 Springer Publishing Company, LLC. 15  Alcohols Have a generic formula of R–O–H Functional group is the hydroxyl group, O–H Alcohol Since the hydroxyl group is covalently bonded to the carbon chain, alcohols do not contain a hydroxide ion Alcohols are not strong bases Have a hydrogen atom directly bonded to an oxygen atom Alcohols can form hydrogen bonds If the R group contains three or fewer carbon atoms, the alcohol is perfectly soluble in water Aromatic alcohols are called phenols 16 © 2017 Springer Publishing Company, LLC. Aromatics Sometimes called arenes Have a functional group called a benzene ring Very common in nature because they are especially stable Frequently a structural element in medications Benzene is the archetype aromatic compound and has the molecular formula C6H6 When a benzene ring is a stick-on group, it is called a phenyl group ASA, Nicotine, Diazepam 17 © 2017 Springer Publishing Company, LLC.  Phenols are similar to alcohols in that they both have the general formula ROH. Phenols The R in phenols represents an aryl group (Ph-OH) (benzene). A simple phenol is polar due to the hydroxyl group, but more complex phenols such as propofol (diisopropyl phenol) are not water soluble Common drugs Morphine, epinephrine Metabolites glucuronides and sulfates 18 © 2017 Springer Publishing Company, LLC.  Ethers have the general formula ROR′, where R and R′ are alkyl groups attached by oxygen. Ethers are inert and do not react with oxidizing or reducing agents, but are highly Ethers flammable. (-C-O-C-) Both alkyl groups of the outdated anesthetic agent diethyl ether are bonded to oxygen Halogen substitution on ethers alters anesthetic characteristics (such as blood solubility and potency) while lowering flammability. Example- diphenhydramine; diethyl ether 19 © 2017 Springer Publishing Company, LLC.  The carbonyl group, though not Carbonyl a functional group by itself, is a key component of the following Groups functional groups: aldehydes, (=O) ketones, carboxylic acids, esters, and amides. 20 © 2017 Springer Publishing Company, LLC.  Several functional groups contain a structural arrangement of carbon double bonded to oxygen. Carbonyl This is known as a carbonyl group, and is structurally Groups identified as C=O. The carbonyl group is polar, with the oxygen being more electrically negative. 21 © 2017 Springer Publishing Company, LLC.  Alkanes (C-C) Also known as paraffins Simplest of the organic compounds Characterized by carbon-carbon single bonds Hydrocarbo Are the carbon backbone for other functional groups n Functional Methane (CH4) is the simplest alkane Groups Ethane (CH3–CH3) is the next member of the alkane family Propane Not water soluble Hydrophobic/ water fearing Lipophilic/Lipid loving 22 © 2017 Springer Publishing Company, LLC.  Also known as olefins Have a carbon-carbon double bond functional group Simplest is ethene and ethylene The location of the double bond is given by a locant number Alkenes Identifies the first carbon in the C=C double bond The 1 double bond makes converts an alkane to an alkene The main functional group always gets the lowest number Drugs that have alkenes Naloxone & Vitamin K 23 © 2017 Springer Publishing Company, LLC.  Also known as acetylenes Have a carbon-carbon triple bond functional group Alkynes Relatively rare in medical settings Simplest is ethyne (more commonly known as acetylene) 24 © 2017 Springer Publishing Company, LLC.  Water soluble Amides Similar to esters (- C(=))NRR PCN, LSD, and Lidocaine ’) Carbonyl carbon atom singly bonded to a nitrogen atom 25 © 2017 Springer Publishing Company, LLC.  Carbonyl group attached to a alkoxy Esters (- group ie single bond to an oxygen atom C(=O)OR Increased , -CO2R) lipophilicity which increases absorption of the drug. 26 © 2017 Springer Publishing Company, LLC. Stereochemistry Stereochemistry is the study of how molecules are structured in three dimensions Chirality is a unique subset of stereochemistry, and the term chiral is used to designate a molecule that has a center (or centers) of three-dimensional asymmetry. This kind of molecular configuration is almost always a function of the unique, tetrahedral bonding characteristics of the carbon atom.  Stereochemistry Enantiomers (substances When the two enantiomers of opposite shape) are a are present in equal pair of molecules existing in mepivacaine, bupivacaine, proportions (50:50), they Usually local anesthetics/ two forms that are mirror ropivacaine, are referred to as a Amides/Chiral images of one another levobupivacaine racemic mixture or pure (right and left hand) but isomers cannot be superimposed  Structure Activity Relationships Most carbon based compounds can have Receptors can and do Stereoisomers can the same chemical show preference for have different effects structure but different one form over another and side effects arrangement of their bonds. (stereoisomers) Structure Drug manufacturers take advantage of this Activity to alter compounds in new ways which Relationships results in a new compound that has different affinity and effects on the body Most of the compounds that are metabolically active are the S type Pure S enantiomers less cardiotoxic & neurotoxic than the racemic mix of R enantiomers Some Basic Terminology Solution—homogeneous mixture that consists of Homogeneous mixture Phase boundary— Solute—the material one or more solutes —not possible to separates regions of a that got dissolved; the uniformly dispersed at discern phase mixture where the component of the the molecular or ionic boundaries between the chemical or physical solution present in the level throughout a components of the properties of the smaller quantity medium known as the mixture mixture change solvent Air is a solution of Mixtures of oxygen and Solvent—material that Solutions aren’t nitrogen, oxygen, and a nitrous oxide are also does the dissolving necessarily liquids few other minor gases solutions Copyright © Springer Publishing Company, 31 LLC. All Rights © 2017 Springer Publishing Company, LLC. Solubility The degree of solubility is difficult to predict, however it is based on the following: The magnitude of difference between polarity of the solute and solvent ie rule of dissolves like… Temperature- An increase in temperature usually, but not always increases solubility Pressure. Pressure has little effect on solubility of solids and liquids in liquids. However, the solubility of gases in solution is extremely pressure dependent. Solubility A saturated solution contains the maximum amount of a solute, as defined by its solubility. No more solute will dissolve in a solution saturated with that solute. If the solution is not saturated, more solute will dissolve in that solution. Sometimes, a solution will become supersaturated with a solute. A supersaturated solution contains more solute than allowed by the solubility of the solute. This is not a stable system, because there is more solute dissolved in the sample than the solvent can accommodate. In this case, the excess solute will come out of solution crystallizing as a solid, separating as a liquid, or bubbling out as a gas.  Oil and Water immiscible Water and alcohol and miscible Solubility Lidocaine (a nonpolar, water-insoluble organic compound) reacts with hydrochloric acid to give an ionic salt, which is called lidocaine hydrochloride. Because lidocaine hydrochloride has an ionic bond, it is readily soluble in water. Cocaine hydrochloride is a highly crystalline, water-soluble species suitable for direct introduction into the user. However, cocaine hydrochloride, like all ionic compounds, has a very low vapor pressure and is not suitable for smoking. Therefore, a base such as ammonia or sodium bicarbonate (baking soda) is added to convert the salt to the more volatile free-base form. If the process doesn’t include removing the inorganic by-products, the result is crack cocaine. Aqueous Solutions Water is the most abundant solvent in the world Water molecules are polar and an excellent solvent for other substances Colloids A colloidal suspension is not a true solution; the colloid particles are not identical in size nor homogeneously distributed throughout the solution. Think of PRBC… Aqueous Solutions The role of water in the solution process deserves special attention. It is often referred to as the “universal solvent” because of the large number of ionic and polar covalent compounds that are at least number of ionic and polar covalent compounds that are at least It is the principal biological solvent. These characteristics are a direct consequence of the molecular geometry and structure of water and its ability to undergo hydrogen bonding. Aqueous Solutions Concentration of charge in these electrolytic solutions is even more important than the molar concentration of the ions that are responsible for the charge. Consequently, we often use concentration units (eq/L and meq/L) that emphasize charge rather than number of ions in solution  Aqueous Solutions MolaRity is the most commonly used concentration unit and is temperature dependent. MolaLity, or molal concentration, expresses concentration in terms of moles of solute per kilogram of solvent. Molality can be used as a conversion factor between moles of solute and kilograms of solvent. Molality is abbreviated with a lowercase m. Notice we said kilograms of solvent, not kilograms of solution. Aqueous There are four commonly cited colligative Solutions properties: The vapor pressure of a solution decreases with increasing solute concentration. The boiling point of a solution increases with increasing solute concentration. The freezing point of a solution decreases with increasing solute concentration. The osmotic pressure of a solution increases with increasing solute concentration. Biological The most important cations in body fluids Effects of are Na+ and K+ Electrolytes in Na+ is the most abundant in blood and Solution intracellular fluids K+ is the most abundant intracellular Intracellular/blood Na+ is 135 meq/L and K+ is 3.5-5.0 meq/L Inside the cell K+ is 125 meq/L and Na+ is 10meq/L Acids & Bases An acid is a species that increases the hydronium ion (H3O+) concentration in an aqueous solution. A base is a species that increases the hydroxide ion (OH−) concentration in an aqueous solution. Acid and Base The Arrhenius theory was proposed in the late 1800s to describe general characteristics of acids and bases. According to this early theory, when an Arrhenius acid dissolves in water, it dissociates to form hydrogen ions or protons (H+), and when an Arrhenius base dissolves in water, it dissociates to form hydroxide ions (OH−). Acid and Base According to this inclusive theory, a Brønsted-Lowry acid is defined as a proton donor Brønsted-Lowry base is defined as a proton acceptor. pH The pH scale correlates the hydronium ion concentration with a number, the pH, that serves as a useful indicator of the degree of acidity or pH= -log[H+] basicity of a solution. The pH of a solution is defined as the negative logarithm of the molar concentration of the hydronium ion (pH = −log[H3O+]) Law of Mass Action The driving force for both forward and backward (chemical) reactions is equal when the mixture is at equilibrium Acid-Base and Acid base reactions involve the Oxidation- transfer of a hydrogen ion H+ Reduction from one reactant to another Reactions Another important reaction type, oxidation and reduction, takes place because of the transfer of one or more electrons from one reactant to another  An acid and base on the opposite sides of the equation are collectively termed a conjugate acid-base pair. Conjugate The two conjugate acid-base pairs in this reaction are acid-base pair HX/X− and HY+/Y. Acid Base When dissolved in water, the dissociation of the acid (or base) produces ions that can conduct an electric current. The strength of an acid (or base) is measured by the degree of dissociation of the acid (or base) in solution. As a result of the differences in the degree of dissociation, strong acids and bases are strong electrolytes while weak acids and bases are weak electrolytes. It is important to note that acid (or base) strength is independent of acid (or base) concentration. Recall that concentration refers to the amount of solute (in this case, the quantity of acid or base) per quantity of solution. Acid Base The strength of an acid (or base) in an aqueous solution depends on the extent to which it reacts with the solvent, water. Although in several reactions, we show the forward and reverse arrows to indicate the reversibility of the reaction, seldom are the two processes “equal but opposite.” One reaction, either forward Acid and Base IF you put a strong acid or a strong base in water it will ionize completely IF you put a weak acid or a weak base in water, a fraction of it will be ionized and the remaining fraction will be unionized Acid–Base Reactions Involve a transfer of a hydrogen ion from the acid to the base In order to predict the products of an acid–base reaction: Identify which is the acid and which is the base Move an H+ ion from the acid to the base, converting the acid into its conjugate base and the base into its conjugate acid Any acid–base reaction has two acids and two bases: One acid and one base on the reactant side Conjugate acid and conjugate base on the product side The base almost always has a lower (more negative) charge than the acid Also, hydrogen is almost always the first atom listed in the formula of an acid The reaction equilibrium always favors the formation of the weaker acid Look up the Ka’s for the reacting acid and the conjugate acid of the reacting base © 2017 Springer Publishing Company, LLC. 52 Ionization Ionization describes the process where a molecule gains a positive or negative charge The amount of ionization is dependent on 2 things: The pH of the solution The pKa of the drug pKa The pKa sets the equilibrium (50:50) reference point An environment with a pH < pKa is a relatively acidic environment for the drug An environment with a pH > pKa is a relatively basic environment for the drug The relationship of the drugs pKa to the pH of the drug’s environment determines the proportion of ionized to nonionized drug What happens when you An acidic drug will be highly place an ACID ionized in a basic pH in a BASIC Solution? The acidic drug wants to donate protons and the basic solution want to accept protons The acidic drug happily donates its protons and will become ionized What happens when you An acidic drug will be highly place an ACID unionized in an acidic pH in a ACIDIC Solution? The acidic drug wants to donate protons and the acid solution wants to do the same Since there are no proton acceptors, the acidic drug retains its proton and will remain unionized Ionization of Weak Acids/Strong Base Drug X has pKa= 3.5 Drug X has pKa= 8.5 More Nonionized More Ionized Acids Donate H+/UnProtonated/conjugate base Base Accepts OH-/Protonated/conjugate acid pH 1.0 7.4 14 More Acidic More Basic pHpKa Lipid soluble Water soluble Cross BBB Does NOT cross BBB Drugs and Acids/Base Most drugs are weak acids or weak bases They are usually prepared as a salt that dissociated in solution A weak acid is paired with a positive ion ie Na+ Ca+ Magnesium A weak base is paired with a negative ion such as chloride or sulfate  K= Ka is an equilibrium Kb is an equilibrium Equilibrium constant governing constant governing the ionization of the ionization of weak acids. weak bases. As K decreases, the As K increases, the reaction tends to reaction tends to increasingly favor increasingly favor starting materials, products. That is, and the reverse the forward reaction reaction becomes becomes more more favorable. favorable. Strategy for Acid-Base Problems A weak acid or weak base Non-ionized drug is problem will lipid soluble- typically ask you to readily crosses determine if a drug is present BBB to a greater extent in the Ionized form is nonionized form or the ionized water form soluble/hydrophilic Determination Weak Acid Nonionized when pH decreases Ionized when pH increases Weak Base Nonionized when pH increases Ionized when pH decreases The pKa is your reference; when the pH of an aqueous solution is the same as the pKa of the drug pKa=pH when the drug is 50% ionized and 50% nonionized Buffer A buffer solution contains components that enable the solution to resist large changes in pH when acids or bases are added. Buffer action relies on the equilibrium between either a weak acid and its conjugate base or a weak base and its conjugate acid. LeChatelier’s principle, which states that an equilibrium system, when stressed, will shift its equilibrium position to alleviate that stress. LeChatelier’s Principle When a system at equilibrium is subjected to change in concentration, temperature, volume, or pressure, then the equilibrium readjusts itself to counteract the effect of the applied change and a new equilibrium is established. LeChatelier’s Principle The solubility of a salt such as NaCl in water increases with increasing temperature When the concentration of a reactant is increased (or the concentration of a product is decreased) the reaction is driven toward the production of more products When the concentration of a reactant is decreased (or the concentration of a product is increased) the reaction is driven toward the production of less products Buffer Buffering against base is a function of the concentration of the weak acid for an acidic buffer, whereas buffering against acid is dependent on the concentration of the anion of the salt (conjugate base) Buffer capacity is a measure of the ability of a solution to resist large changes in pH when a strong acid or strong base is added Buffer A buffer solution can be described by an equilibrium constant expression. The equilibrium constant expression for an acidic system can be rearranged and solved for [H3O+]. In that way, the pH of a buffer solution can be obtained, if the composition of the solution is known.  A pH buffer is a solution that resists changes in pH It contains a weak acid (HA) and its conjugate base (A−) or a weak base and its conjugate acid Buffer solutions resist change in pH If a strong base is added to a buffered solution, the weak acid in the buffer HA reacts with the hydroxide ion to give water and the weak base A− HA + OH− ⇄ H2O + A− This results in converting a strong base OH− into a Buffers weak base A− The pH increases, but not by much If a strong acid is added to a buffered solution, the weak base in the buffer (A− ) reacts with the H+ ion to give HA A− + H+ ⇄ HA This results in converting a strong acid H+ into a weak acid HA The pH decreases, but not by much © 2017 Springer Publishing Company, LLC. 68 Buffers (Cont’d) Calculating the pH of a Buffer The pH of a buffer is determined by the acid strength of HA As the acid strength of HA increases, the pH range maintained by a buffer system based on HA decreases Equation for the acid ionization of HA: HA ⇄ H+ + A− The equilibrium constant expression for this equilibrium is: The equilibrium state can be achieved from an infinite number of starting points The Henderson–Hasselbach equation, or buffer equation is: This equation can be used to calculate the pH of a buffer or to determine the ratio of weak acid to conjugate base at a given pH © 2017 Springer Publishing Company, LLC. 69  Strong Acids Very determined to foist their proton off onto a base Essentially 100% ionized when dissolved in water, but this is not an equilibrating process, so all of the starting materials are converted into products Strong acids are relatively rare Strong Bases Acids and In water, the strongest possible base is the hydroxide ion, OH− A strong base ionizes essentially 100% to produce the OH − ion, so a strong base is a soluble ionic hydroxide Bases Weak Acids Are able to donate hydrogen ions to bases, but are less determined to do so than strong acids Summary When a weak acid dissolves in water, it establishes a dynamic equilibrium between the molecular form of the acid and the ionized form Weak Bases Are able to accept hydrogen ions from acids, but are less determined to do so than strong bases Do not completely ionize in water to produce an equivalent concentration of the hydroxide ion, because when a weak base dissolves in water, it establishes a dynamic equilibrium between the molecular form and the ionized form 70 © 2017 Springer Publishing Company, LLC.  Acid and Base Strength: Ka and Kb Some acids are stronger than others A stronger acid is more determined to give its proton to some base A stronger base is more determined to take a proton from some acid Acids and When a strong acid dissolves in water, it dissociates completely All other acids are weak acids Bases The relative strength of a weak acid is quantified by the equilibrium constant Ka governing the ionization of the weak acid Summary A larger value of Ka means a stronger acid Acid/Base Strength of Conjugate Acid–Base Pairs The stronger the acid, the weaker its conjugate base The stronger the base, the weaker its conjugate acid General guidelines The conjugate base of a really strong acid has no base strength The conjugate base of a weak acid has base strength The conjugate acid of a weak base has acid strength 71 © 2017 Springer Publishing Company, LLC. Metabolism Pathways 4 B A S I C PAT H WAYS O F M E TA B O L I S M P H A S E 1 A N D PH A S E 2 R E ACTI O N S Oxidation Phase 1 Reduction Oxidation, Reduction, & Hydrolysis Hydrolysis Increases polarity Conjugation Phase 2 Conjugation Increases solubility Reactions Phase I: oxidation reduction, hydrolysis: increases the drugs polarity prior to phase II reaction Phase II conjugation reactions that covalently link the drug or metabolites with a highly polar molecule (carbohydrate or an amino acid) that renders the conjugate more water- soluble for subsequent excretion Sites of Hepatic microsomal enzymes are Metabolism responsible for the metabolism of most drugs. Other sites of drug metabolism include the plasma (Hofmann elimination, ester hydrolysis), lungs, kidneys, and gastrointestinal tract and placenta (tissue esterases). Oxidation- Oxidation the loss of electrons, loss of hydrogen Reduction atoms or gain of oxygen atoms Process Reduction the gain of electrons, gain of hydrogen or Same in the loss of oxygen atoms metabolism Oxidation and reduction are complementary Review processes. The oxidation half-reaction produces one or more electrons that are the reactants for the reduction half- reaction. The combination of two half-reactions, one oxidation and one reduction, produces the complete oxidation- reduction reaction Phase 1 Cytochrome P450 (CYP) enzymes, non-CYP enzymes, and flavin-containing monooxygenase enzymes Enzymes The CYP enzyme system is a large family of membrane- bound proteins containing a heme cofactor that catalyzes the metabolism of compounds The P450 enzymes are predominantly hepatic microsomal enzymes, although there are also mitochondrial P450 enzymes The P450 3A4 metabolizes more than one-half of all currently available drugs, including opioids (alfentanil, sufentanil, fentanyl), benzodiazepines, local anesthetics (lidocaine, ropivacaine), immunosuppressants (cyclosporine), and antihistamines (terfenadine). Phase I Induction occurs through increased Enzymes expression of the enzymes. For example, phenobarbital induces microsomal enzymes and thus can render drugs less effective through increased metabolism Conversely, other drugs directly inhibit enzymes, increasing the exposure to their substrates. Famously, grapefruit juice (not exactly a drug) inhibits CYP 3A4, possibly increasing the concentration of anesthetics and other drugs. Phase I: Oxidation These enzymes require an electron donor in the form of reduced nicotinamide adenine dinucleotide and molecular oxygen for their activity. Examples of oxidative metabolism of drugs catalyzed by CYP enzymes include hydroxylation, deamination, desulfuration, dealkylation, and dehalogenation. Demethylation of morphine to normorphine is an example of oxidative dealkylation. Phase I: Reduction Under conditions of low oxygen partial pressures, CYP enzymes transfer electrons directly to a substrate such as halothane rather than to oxygen. This electron gain imparted to the substrate occurs only when insufficient amounts of oxygen are present to compete for electrons. Phase II: Conjugation with glucuronic acid Conjugation involves CYP enzymes. Glucuronic acid is synthesized from glucose and added to lipid-soluble drugs to render them water-soluble The resulting water-soluble glucuronide conjugates are then excreted in bile and urine. Reason for hyperbilirubinemia in neonates Phase I: Hydrolysis Enzymes responsible for hydrolysis of drugs, usually at an ester bond, do not involve the CYP enzymes system. Hydrolysis often occurs outside of the liver. For example, remifentanil, succinylcholine, esmolol, and the ester local anesthetics are cleared in the plasma and tissues via ester hydrolysis. Phase II Enzymes Glucuronosyltransferases, glutathione-S-transferases, N-acetyl- transferases, and sulfotransferases. Glucuronidation is an important metabolic pathway for several drugs used during anesthesia, including propofol, morphine (yielding morphine- 3-glucuronide and the pharmacologically active morphine-6-glucuronide), and midazolam (yielding the pharmacologically active α1- hydroxymidazolam). Glutathione-S-transferase enzymes are primarily a defensive system for detoxification and protection against oxidative stress. N-acetylation catalyzed by N-acetyl-transferase is a common phase II reaction for metabolism of heterocyclic aromatic amines (particularly serotonin) and arylamines, including the inactivation of isoniazid.  The rate of metabolism for most Hepatic anesthetic drugs is proportional to drug Clearance concentration, rending the clearance of the drug constant (ie, independent of dose). Phase II This is a fundamental assumption for Enzymes anesthetic pharmacokinetics. Exploring this assumption will provide insight into the critical role of clearance in governing the metabolism of drugs. Hepatic Clearance At some rate of drug flow into the liver, the organ will be metabolizing drug as fast as the metabolic enzymes in the organ allow. At this point, metabolism can no longer be proportional to concentration because the metabolic capacity of the organ has been exceeded. Phase II The rate at which drug flows out of the liver must be the same as the Enzymes rate at which drug flows into the liver minus the rate at which the liver metabolizes drug. The rate at which drug flows into the liver is liver blood flow, Q, times the concentration of drug flowing in, Cinflow. The rate at which drug flows out of the liver is liver blood flow, Q, times the concentration of drug flowing out, Coutflow. Hepatic Clearance The rate of hepatic metabolism by the liver, R, is the difference Phase II Enzymes between the drug concentration flowing into the liver and the drug concentration flowing out of the liver, times the rate of liver blood flow: See formula on 2.7 The liver can also become saturated because it does not have an infinite metabolic capacity Clearance is the amount of blood completely cleared of drug per unit time. Genetic Special consideration that affects metabolism: metabolism Slow vs Fast acetylators (phase II reaction) Slow: more prone to toxicity with amides Caucasian: 50% fast acetylators African American: 50% slow acetylators Asian: 60-100% fast acetylators (e.g. Japanese 80% fast acetylators) Metabolism Phase I metabolism is enzymatic therefore it can CYPs are a family of be saturated. This happens Occurs in smooth enzymes. There are 50 when too much or different endoplasmic reticulum types collectively known as drugs that use the same located in hepatocytes the CYP-450 system pathway are given in combination. Extraction Ratio The liver cannot remove every last drug molecule. There is always some drug in the effluent plasma The fraction of inflowing drug extracted by the liver is Metabolism Of that system 6 enzymes metabolize 90% of drugs CYP1A2, 2C9, 2C19, 2D6, 3A4 and 3A5. Main reactions in Phase I metabolism are: Hydroxylation Oxidation Reduction Hydrolysis Some drugs undergo more than one reaction Metabolism Some drugs increase the amounts of available enzymes this is known as induction resulting in shorter than anticipated half- life Some drugs inhibit these enzymes resulting in prolongation of half-life Metabolism Phase 2 reactions- also known as synthetic reactions Polar molecules are attached to the compounds being metabolized Most, not all, drugs undergo phase 1 reactions and then phase 2 Common phase 2 reactions involve the attachment of a sugar group to the molecule this renders the compound water soluble Metabolism Some drugs rely on phase 2 metabolism to inactivate the drug. First pass metabolism- orally given drugs are carried via portal vein circulation to the liver where they get metabolized. By definition the bioavailability of IV drugs is 1 Extraction Ratio When clearance is flow limited, it is generally unaffected by modest changes in hepatic capacity. However, when clearance is capacity limited, changes in liver metabolic capacity produce nearly proportional changes in clearance rate. For these drugs, clearance can be significantly decreased by hepatic disease or increased by enzymatic induction. Renal Clearance GFR Active tubular secretion Passive tubular reabsorption Renal The amount of drug that enters the renal tubular Clearance lumen depends on the fraction of drug bound to protein and the glomerular filtration rate (GFR). Renal tubular secretion involves active transport processes, which may be selective for certain drugs and metabolites, including protein-bound compounds. Reabsorption from renal tubules removes drug that has entered tubules by glomerular filtration and tubular secretion. This reabsorption is most prominent for lipid- soluble drugs that can easily cross cell membranes of renal tubular epithelial cells to enter pericapillary fluid. Absorption Will be discussed with inhaled anesthetic drugs Not relevant for most anesthetic drugs  Most drugs are weak acids or bases that are present in both ionized and nonionized forms in solution. Ionization The nonionized molecule is usually lipid soluble and can diffuse across cell membranes including the blood–brain barrier, renal tubular epithelium, gastrointestinal epithelium, placenta, and hepatocytes As a result, it is usually the nonionized form of the drug that is pharmacologically active, undergoes reabsorption across renal tubules, is absorbed from the gastrointestinal tract, and is susceptible to hepatic metabolism. Conversely, the ionized fraction is poorly lipid soluble and cannot penetrate lipid cell membranes easily A high degree of ionization thus impairs absorption of drug from the gastrointestinal tract, limits access to drug-metabolizing enzymes in the hepatocytes, and facilitates excretion of unchanged drug, as reabsorption across the renal tubular epithelium is unlikely Ionized vs Nonionized Determinants of Ionization The degree of drug ionization is a function of its dissociation constant (pK) and the pH of the surrounding fluid. When the pK and the pH are identical, 50% of the drug exists in both the ionized and nonionized form. Small changes in pH can result in large changes in the extent of ionization, especially if the pH and pK values are similar Ion Trapping Because it is the nonionized drug that equilibrates across lipid membranes, a concentration difference of total drug can develop on two sides of a membrane that separates fluids with different pHs because the ionized concentrations will reflect the local equilibration between ionized and nonionized forms based on the pH. This is an important consideration because one fraction of the drug may be more pharmacologically active than the other fraction. This will be discussed further in Pharm 2 with local anesthetics and Peds/Ob during specific pharmacology  Ion trapping and extraction ratio featured, somewhat unexpectedly, in the trial of Conrad Murray for the death of Famous Michael Jackson. Ion Trapping The initial defense strategy was to blame Michael Jackson for his death, claiming that he drank a mixture of propofol and Example lidocaine when Conrad Murray stepped out of the room. We already know why the propofol claim is bogus. As discussed earlier, the extraction ratio for propofol is nearly 1 ie high. (a change in liver blood flow produces a nearly proportional change in clearance) The extraction ratio does not care if the propofol enters the liver from the hepatic artery or portal vein. The liver will just as happily remove all the propofol from the portal vein as from the hepatic artery. As a result, any propofol that is swallowed will be metabolized in the liver before ever reaching the systemic circulation.  Water accounts for: Man 60% Woman 50% Body Composition Neonate 70% Total water is less in women and obese individuals Elderly less water higher lipid Body Composition- Interstitial Plasma 3L Blood 5L Daily water intake is 2.5L 1.5L is lost through urine 100mL sweat 100mL feces 300-400mL lungs greatest cold environments & least heat 400mL lost by diffusion through the skin/ not sweat Body fluid compartments  Osmosis is the movement of water (solvent molecules) across a semipermeable membrane from a compartment in which the nondiffusible solute (ion) concentration is lower to a compartment in which the solute concentration is higher Osmosis The lipid bilayer that surrounds all cells is freely permeable to water but is impermeable to ions. As a result, water rapidly moves across the cell membrane to establish osmotic equilibration, which happens almost instantly.  Most capillary walls are permeable to small solutes (Na, Cl) so small solutes do not exert an osmotic effect. The BBB are exceptions Movement of Albumin does not permeate the capillary Water Across wall Capillary Will Albumin provides osmotic pressure in blood Albumin is the major determinant for intravascular volume Osmosis  Osmole is the unit used to express osmotic pressure in solutes, but the denominator for osmolality is kilogram of water. Osmolarity is the correct terminology when osmole Osmolality concentrations are expressed in liters of body fluid (eg, plasma) rather than kilograms of water. Plasma osmolarity is important in evaluating dehydration, overhydration, and electrolyte abnormalities. Osmolarity Normal plasma has an osmolarity of about 290 mOsm/L. All but about 20 mOsm of the 290 mOsm in each liter of plasma are contributed by sodium ions and their accompanying anions, principally chloride and bicarbonate. Proteins normally contribute