Pharmacokinetics.pdf

Pharmacology Introduction to Pharmacology Pharmacokinetics #1 Introduction to Pharmacology Pharmacology: Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting nor...

Pharmacology Introduction to Pharmacology Pharmacokinetics #1 Introduction to Pharmacology Pharmacology: Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. The interactions between a drug and the body are conveniently divided into two classes. The actions of the drug on the body are termed pharmacodynamic processes. These properties determine the group in which the drug is classified, and they play the major role in deciding whether that group is appropriate therapy for a particular symptom or disease. Introduction to Pharmacology Pharmacology: The actions of the body on the drug are called pharmacokinetic processes. Pharmacokinetic processes govern the absorption, distribution, and elimination of drugs and are of great practical importance in the choice and administration of a particular drug for a particular patient, eg, a patient with impaired renal function. Introduction to Pharmacology Introduction to Pharmacology Pharmacokinetics: Absorption: First, absorption from the site of administration permits entry of the drug (either directly or indirectly) into plasma. Distribution: Second, the drug may then reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids. Metabolism: Third, the drug may be bio-transformed by metabolism by the liver or other tissues. Elimination: Finally, the drug and its metabolites are eliminated from the body in urine, bile, or feces. Introduction to Pharmacology Pharmacokinetics: Note: Using knowledge of pharmacokinetic parameters, clinicians can design optimal drug regimens, including the route of administration, the dose, the frequency, and the duration of treatment. Routes of Drugs Administration Routes of Drugs Administration The route of administration is determined by properties of the drug and by the therapeutic objectives (for example, the need for a rapid onset, the need for longterm treatment, or restriction of delivery to a local site). Major routes of drug administration include enteral, parenteral, and topical, among others. Routes of Drugs Administration A. Enteral: Enteral administration (administering a drug by mouth) is the safest and most common, convenient, and economical method of drug administration. The drug may be swallowed, allowing oral delivery, or it may be placed under the tongue (sublingual), or between the gums and cheek (buccal), facilitating direct absorption into the bloodstream. Routes of Drugs Administration A. Enteral: 1. Oral: Oral administration provides many advantages. Oral drugs are easily self-administered, and toxicities and/or overdose of oral drugs may be overcome with antidotes, such as activated charcoal. However, the pathways involved in oral drug absorption are the most complicated, and the low gastric pH inactivates some drugs. A wide range of oral preparations is available including enteric-coated and extendedrelease preparations. Routes of Drugs Administration A. Enteral: Routes of Drugs Administration A. Enteral: 1. Oral: a. Enteric-coated Preparations: An enteric coating is a chemical envelope that protects the drug from stomach acid, delivering it instead to the less acidic intestine, where the coating dissolves and releases the drug. Enteric coating is useful for certain drugs (for example, omeprazole) that are acid labile, and for drugs that are irritating to the stomach, such as aspirin. Routes of Drugs Administration A. Enteral: 1. Oral: a. Enteric-coated Preparations: Routes of Drugs Administration A. Enteral: 1. Oral: b. Extended-release Preparations: Extended-release (abbreviated ER, XR, XL, SR, etc.) medications have special coatings or ingredients that control drug release, thereby allowing for slower absorption and prolonged duration of action. ER formulations can be dosed less frequently and may improve patient compliance. In addition, ER formulations may maintain concentrations within the therapeutic range over a longer duration, as opposed to immediate release dosage forms, which may result in larger peaks and troughs in plasma concentration. Routes of Drugs Administration A. Enteral: 1. Oral: b. Extended-release Preparations: ER formulations are advantageous for drugs with short half-lives. For example, the half-life of oral morphine is 2 to 4 hours, and it must be administered six times daily to provide continuous pain relief. However, only two doses are needed when extended-release tablets are used. Routes of Drugs Administration b. Extended-release Preparations: Routes of Drugs Administration A. Enteral: 2. Sublingual / Buccal: The sublingual route involves placement of drug under the tongue. The buccal route involves placement of drug between the cheek and gum. Both the sublingual and buccal routes of absorption have several advantages,including: 1. ease of administration. 2. rapid absorption. 3. bypass of the harsh gastrointestinal (GI) environment. 4. avoidance of first-pass metabolism. Routes of Drugs Administration A. Enteral: 2. Sublingual / Buccal: Routes of Drugs Administration B. Parenteral: The parenteral route introduces drugs directly into the body by the injection. Parenteral administration is used for drugs that are poorly absorbed from the GI tract (for example, heparin) or unstable in the GI tract (for example, insulin). Parenteral administration is also used if a patient is unable to take oral medications (unconscious patients) and in circumstances that require a rapid onset of action. Routes of Drugs Administration B. Parenteral: In addition, parenteral routes have the highest bioavailability and are not subject to firstpass metabolism or the harsh GI environment. Parenteral administration provides the most control over the actual dose of drug delivered to the body. However, these routes of administration are irreversible and may cause pain, fear, local tissue damage, and infections. The four major parenteral routes are intravascular (intravenous or intra-arterial), intramuscular, and subcutaneous, and intradermal. Routes of Drugs Administration B. Parenteral: Routes of Drugs Administration B. Parenteral: Routes of Drugs Administration B. Parenteral: 1. Intravenous (IV): IV injection is the most common parenteral route. It is useful for drugs that are not absorbed orally, such as the neuromuscular blocker rocuronium. IV delivery permits a rapid effect and a maximum degree of control over the amount of drug delivered. Routes of Drugs Administration B. Parenteral: 1. Intravenous (IV): When injected as a bolus, the full amount of drug is delivered to the systemic circulation almost immediately. If administered as an IV infusion, the drug is infused over a longer period, resulting in lower peak plasma concentrations and an increased duration of circulating drug. Routes of Drugs Administration B. Parenteral: 2. Intramuscular (IM): Drugs administered IM can be in aqueous solutions, which are absorbed rapidly, or in specialized depot preparations, which are absorbed slowly. Depot preparations often consist of a suspension of drug in a nonaqueous vehicle, such as polyethylene glycol. As the vehicle diffuses out of the muscle, drug precipitates at the site of injection. The drug then dissolves slowly, providing a sustained dose over an extended interval. Routes of Drugs Administration B. Parenteral: 2. Intramuscular (IM): Routes of Drugs Administration B. Parenteral: 3. Subcutaneous (SC): Like IM injection, SC injection provides absorption via simple diffusion and is slower than the IV route. SC injection minimizes the risks of hemolysis or thrombosis associated with IV injection and may provide constant, slow, and sustained effects. This route should not be used with drugs that cause tissue irritation, because severe pain and necrosis may occur. Drugs commonly administered via the subcutaneous route include insulin and heparin. Routes of Drugs Administration B. Parenteral: 3. Subcutaneous (SC): Routes of Drugs Administration B. Parenteral: 4. Intradermal: The intradermal (ID) route involves injection into the dermis, the more vascular layer of skin under the epidermis. Agents for diagnostic determination and desensitization are usually administered by this route. Routes of Drugs Administration C. Other: 1. Oral Inhalation and Nasal Preparations: Both the oral inhalation and nasal routes of administration provide rapid delivery of drug across the large surface area of mucous membranes of the respiratory tract and pulmonary epithelium. Drug effects are almost as rapid as are those with IV bolus. Drugs that are gases (for example, some anesthetics) and those that can be dispersed in an aerosol are administered via inhalation. Routes of Drugs Administration C. Other: 1. Oral Inhalation and Nasal Preparations: This route is effective and convenient for patients with respiratory disorders such as asthma or chronic obstructive pulmonary disease, because drug is delivered directly to the site of action, thereby minimizing systemic side effects. The nasal route involves topical administration of drugs directly into the nose, and it is often used for patients with allergic rhinitis. Routes of Drugs Administration C. Other: 2. Intrathecal / Intraventricular: The blood-brain barrier typically delays or prevents the absorption of drugs into the central nervous system (CNS). When local, rapid effects are needed, it is necessary to introduce drugs directly into the cerebrospinal fluid. Routes of Drugs Administration 2. Intrathecal / Intraventricular: Routes of Drugs Administration C. Other: 3. Topical: Topical application is used when a local effect of the drug is desired. Routes of Drugs Administration C. Other: 4. Transdermal: This route of administration achieves systemic effects by application of drugs to the skin, usually via a transdermal patch. The rate of absorption can vary markedly, depending on the physical characteristics of the skin at the site of application, as well as the lipid solubility of the drug. Routes of Drugs Administration C. Other: 4. Transdermal: Routes of Drugs Administration C. Other: 5. Rectal: Because 50% of the drainage of the rectal region bypasses the portal circulation, the biotransformation of drugs by the liver is minimized with rectal administration. The rectal route has the additional advantage of preventing destruction of the drug in the Gl environment. This route is also useful if the drug induces vomiting when given orally, if the patient is already vomiting, or if the patient is unconscious. Routes of Drugs Administration C. Other: 5. Rectal: Rectal absorption is often erratic and incomplete, and many drugs irritate the rectal mucosa. Following figure summarizes characteristics of the common routes of administration, along with example drugs. Routes of Drugs Administration Routes of Drugs Administration Routes of Drugs Administration Routes of Drugs Administration Absorption of Drugs Absorption of Drugs Absorption is the transfer of a drug from the site of administration to the bloodstream. The rate and extent of absorption depend on the environment where the drug is absorbed, chemical characteristics of the drug, and the route of administration (which influences bioavailability). Routes of administration other than intravenous may result in partial absorption and lower bioavailability. Absorption of Drugs A. Mechanisms of Absorption of Drugs from the GI Tract: Depending on their chemical properties, drugs may be absorbed from the GI tract by passive diffusion, facilitated diffusion, active transport, or endocytosis. 1. Passive Diffusion: The driving force for passive diffusion of a drug is the concentration gradient across a membrane separating two body compartments. In other words, the drug moves from an area of high concentration to one of lower concentration. Absorption of Drugs A. Mechanisms of Absorption of Drugs from the GI Tract: 1. Passive Diffusion: Passive diffusion does not involve a carrier, is not saturable, and shows low structural specificity. The vast majority of drugs are absorbed by this mechanism. Water-soluble drugs penetrate the cell membrane through aqueous channels or pores, whereas lipid-soluble drugs readily move across most biologic membranes due to solubility in the membrane lipid bilayers. Absorption of Drugs A. Mechanisms of Absorption of Drugs from the GI Tract: 2. Facilitated Diffusion: Other agents can enter the cell through specialized transmembrane carrier proteins that facilitate the passage of large molecules. These carrier proteins undergo conformational changes, allowing the passage of drugs or endogenous molecules into the interior of cells. This process is known as facilitated diffusion. It does not require energy, can be saturated, and may be inhibited by compounds that compete for the carrier. Absorption of Drugs A. Mechanisms of Absorption of Drugs from the GI Tract: 2. Facilitated Diffusion: Absorption of Drugs A. Mechanisms of Absorption of Drugs from the GI Tract: 3. Active Transport: This mode of drug entry also involves specific carrier proteins that span the membrane. However, active transport is energy dependent, driven by the hydrolysis of adenosine triphosphate (ATP). It is capable of moving drugs against a concentration gradient, from a region of low drug concentration to one of higher concentration. The process is saturable. Active transport systems are selective and may be competitively inhibited by other cotransported substances. Absorption of Drugs A. Mechanisms of Absorption of Drugs from the GI Tract: 3. Active Transport: Absorption of Drugs A. Mechanisms of Absorption of Drugs from the GI Tract: 4. Endocytosis and Exocytosis: This type of absorption is used to transport drugs of exceptionally large size across the cell membrane. Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug-filled vesicle. Exocytosis is the reverse of endocytosis. Absorption of Drugs A. Mechanisms of Absorption of Drugs from the GI Tract: 4. Endocytosis and Exocytosis: Many cells use exocytosis to secrete substances out of the cell through a similar process of vesicle formation. Vitamin B12 is transported across the gut wall by endocytosis, whereas certain neurotransmitters (for example, norepinephrine) are stored in intracellular vesicles in the nerve terminal and released by exocytosis. Absorption of Drugs B. Factors Influencing Absorption: 1. Effect of pH on Drug Absorption: Acidic drugs (HA) release a proton (H+), causing a charged anion (A−) to form: 𝐻𝐴 ⇆ 𝐻 + + 𝐴− Weak bases (BH+) can also release an H+. However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (B): 𝐵𝐻 + ⇆ 𝐵 + 𝐻 + Absorption of Drugs 1. Effect of pH on Drug Absorption: Figure A – Diffusion of the nonionized form of a weak acid through a lipid membrane. Figure B – Diffusion of the nonionized form of a weak base through a lipid membrane Absorption of Drugs B. Factors Influencing Absorption: 1. Effect of pH on Drug Absorption: Most drugs are either weak acids or weak bases. A drug passes through membranes more readily if it is uncharged. Thus, for a weak acid, the uncharged, protonated HA can permeate through membranes, and A− cannot. For a weak base, the uncharged form B penetrates through the cell membrane, but the protonated form BH+ does not. Absorption of Drugs 1. Effect of pH on Drug Absorption: Distribution of a drug between its ionized and unionized forms depends on the ambient PH and pKa of the drug. Absorption of Drugs B. Factors Influencing Absorption: 1. Effect of pH on Drug Absorption: Therefore, the effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms. The ratio between the two forms is, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base, which is represented by the ionization constant, pKa. Introduction to Pharmacology Pharmacokinetics: Note: The pKa is a measure of the strength of the interaction of a compound with a proton. The lower the pKa of a drug, the more acidic it is. Conversely, the higher the pKa , the more basic is the drug. Distribution equilibrium is achieved when the permeable form of a drug achieves an equal concentration in all body water spaces. Absorption of Drugs B. Factors Influencing Absorption: 2. Blood Flow to the Absorption Site: The intestines receive much more blood flow than the stomach, so absorption from the intestine is favored over the stomach. [ Note: shock severely reduces blood flow to cutaneous tissues, thereby minimizing absorption from SC administration]. 3. Total Surface Area Available for Absorption: With a surface rich in brush borders containing microvilli, the intestine has a surface area about 1000-fold that of the stomach, making absorption of the drug across the intestine more efficient. Absorption of Drugs B. Factors Influencing Absorption: 4. Contact Time at the Absorption Surface: If a drug moves through the GI tract very quickly, as can happen with severe diarrhea, it is not well absorbed. Conversely, anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug. [Note: The presence of food in the stomach both dilutes the drug and slows gastric emptying. Therefore, a drug taken with a meal is generally absorbed more slowly.] Absorption of Drugs B. Factors Influencing Absorption: 5. Expression of P-glycoprotein: P-glycoprotein is a trans-membrane transporter protein responsible for transporting various molecules, including drugs, across cell membranes. It is expressed in tissues throughout the body, including the liver, kidneys, placenta, intestines, and brain capillaries, and is involved in transportation of drugs from tissues to blood. That is, it “pumps” drugs out of the cells. Thus, in areas of high expression, Pglycoprotein reduces drug absorption. In addition to transporting many drugs out of cells, it is also associated with multidrug resistance. Absorption of Drugs B. Factors Influencing Absorption: 5. Expression of P-glycoprotein: Absorption of Drugs C. Bioavailability: Bioavailability is the rate and extent to which an administered drug reaches the systemic circulation. For example, if 100 mg of a drug is administered orally and 70mg is absorbed unchanged, the bioavailability is 0.7 or 70%. Determining bioavailability is important for calculating drug dosages for nonintravenous routes of administration. Absorption of Drugs C. Bioavailability: 1. Determination of Bioavailability: Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (for example, oral administration) with levels achieved by IV administration. After IV administration, 100% of the drug rapidly enters the circulation. When the drug is given orally, only part of the administered dose appears in the plasma. By plotting plasma concentrations of the drug versus time, the area under the curve (AUC) can be measured. Drug Distribution Absorption of Drugs C. Bioavailability: 2. Factors that Influence Bioavailability: In contrast to IV administration, which confers 100% bioavailability, orally administered drugs often undergo first-pass metabolism. This biotransformation, in addition to chemical and physical characteristics of the drug, determines the rate and extent to which the agent reaches the systemic circulation. Absorption of Drugs C. Bioavailability: 2. Factors that Influence Bioavailability: a. First-pass Hepatic Metabolism: When a drug is absorbed from the Gl tract, it enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug entering the systemic circulation is decreased. Absorption of Drugs C. Bioavailability: 2. Factors that Influence Bioavailability: a. First-pass Hepatic Metabolism: This is referred to as first pass metabolism. Drugs with high first-pass metabolism should be given in doses sufficient to ensure that enough active drug reaches the desired site of action. Absorption of Drugs a. First-pass Hepatic Metabolism: Absorption of Drugs C. Bioavailability: 2. Factors that Influence Bioavailability: a. First-pass Hepatic Metabolism: Note: First-pass metabolism by the intestine or liver limits the efficacy of many oral medications. For example, more than 90% of nitroglycerin is cleared during firstpass metabolism. Hence, it is primarily administered via the sublingual, transdermal, or intravenous route. Absorption of Drugs C. Bioavailability: 2. Factors that Influence Bioavailability: b. Solubility of the Drug: Very hydrophilic drugs are poorly absorbed because of the inability to cross lipid-rich cell membranes. Paradoxically, drugs that are extremely lipophilic are also poorly absorbed, because they are insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. For a drug to be readily absorbed, it must be largely lipophilic, yet have some solubility in aqueous solutions. Absorption of Drugs C. Bioavailability: 2. Factors that Influence Bioavailability: b. Solubility of the Drug: This is one reason why many drugs are either weak acids or weak bases. Absorption of Drugs C. Bioavailability: 2. Factors that Influence Bioavailability: c. Chemical Instability: Some drugs, such as penicillin G, are unstable in the pH of gastric contents. Others, such as insulin, are destroyed in the Gl tract by degradative enzymes. Absorption of Drugs C. Bioavailability: 2. Factors that Influence Bioavailability: d. Nature of the Drug Formulation: Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption. Absorption of Drugs D. Bioequivalence and other types of equivalence : Two drug formulations are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations. Two drug formulations are therapeutically equivalent if they are pharmaceutically equivalent (that is, they have the same dosage form, contain the same active ingredient at the same strength, and use the same route of administration) with similar clinical and safety profiles. Thus, therapeutic equivalence requires that drug products are bioequivalent and pharmaceutically equivalent. Drug Distribution Drug Distribution Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and the tissues. For drugs administered IV, absorption is not a factor, and the initial phase (from immediately after administration through the rapid fall in concentration) represents the distribution phase, during which the drug rapidly leaves the circulation and enters the tissues. The distribution of a drug from the plasma to the interstitium depends on cardiac output and local blood flow, capillary permeability, the tissue volume, the degree of binding of the drug to plasma and tissue proteins, and the relative lipophilicity of the drug. Drug Distribution A. Blood Flow: The rate of blood flow to the tissue capillaries varies widely. For instance, blood flow to "vessel-rich organs" (brain, liver, and kidney) is greater than that to the skeletal muscles. Adipose tissue, skin, and viscera have still lower rates of blood flow. Variation in blood flow partly explains the short duration of hypnosis produced by an IV bolus of propofol. Drug Distribution A. Blood Flow: High blood flow, together with high lipophilicity of propofol, permits rapid distribution into the CNS and produces anesthesia. A subsequent slower distribution to skeletal muscle and adipose tissue lowers the plasma concentration so that the drug diffuses out of the CNS, down the concentration gradient, and consciousness is regained. Drug Distribution B. Capillary Permeability: Capillary permeability is determined by capillary structure and by the chemical nature of the drug. Capillary structure varies in terms of the fraction of the basement membrane exposed by slit junctions between endothelial cells. In the liver and spleen, a significant portion of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass. Drug Distribution B. Capillary Permeability: In the brain, the capillary structure is continuous, and there are no slit junctions. To enter the brain, drugs must pass through the endothelial cells of the CNS capillaries or undergo active transport. For example, a specific transporter carries levodopa into the brain. Lipid soluble drugs readily penetrate the CNS because they dissolve in the endothelial cell membrane. By contrast, ionized or polar drugs generally fail to enter the CNS because they cannot pass through the endothelial cells that have no slit junctions. These closely juxtaposed cells form tight junctions that constitute the blood-brain barrier. Drug Distribution B. Capillary Permeability: Drug Distribution C. Binding of Drugs to Plasma Proteins and Tissues: 1. Binding to Plasma Proteins: Reversible binding to plasma proteins sequesters drugs in a non-diffusible form and slows transfer out of the vascular compartment. Albumin is the major drug binding protein, and it may act as a drug reservoir. As the concentration of free drug decreases due to elimination, the bound drug dissociates from albumin. This maintains the free-drug concentration as a constant fraction of the total drug in the plasma. Drug Distribution C. Binding of Drugs to Plasma Proteins and Tissues: 2. Binding to Tissue Proteins: Many drugs accumulate in tissues, leading to higher concentrations in tissues than in interstitial fluid and blood. Drugs may accumulate because of binding to lipids, proteins, or nucleic acids. Drugs may also undergo active transport into tissues. Tissue reservoirs may serve as a major source of the drug and prolong its actions or cause local drug toxicity. (For example, acrolein, the metabolite of cyclophosphamide, can cause hemorrhagic cystitis because it accumulates in the bladder.) Drug Distribution D. Lipophilicity: The chemical nature of a drug strongly influences its ability to cross cell membranes. Lipophilic drugs readily move across most biologic membranes. These drugs dissolve in the lipid membranes and penetrate the entire cell surface. The major factor influencing the distribution of lipophilic drugs is blood flow to the area. By contrast, hydrophilic drugs do not readily penetrate cell membranes and must pass through slit junctions. Drug Distribution E. Volume of Distribution: The apparent volume of distribution, Vd , is defined as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma. It is calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma concentration at time zero (C0 ). 𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑡ℎ𝑒 𝑏𝑜𝑑𝑦 Vd = C0 Although Vd has no physiologic or physical basis, it can be useful to compare the distribution of a drug with the volumes of the water compartments in the body. Drug Distribution E. Volume of Distribution: 1. Distribution into the Water Compartments in the Body: Once a drug enters the body, it has the potential to distribute into any one of the three functionally distinct compartments of body water or to become sequestered in a cellular site. Drug Distribution | E. Volume of Distribution 1. Distribution into the Water Compartments in the Body: a. Plasma Compartment: If a drug has a high molecular weight or is extensively protein bound, it is too large to pass through the slit junctions of the capillaries and, thus, is effectively trapped within the plasma (vascular) compartment. As a result, it has a low Vd that approximates the plasma volume, or about 4 L in a 70-kg individual. Heparin shows this type of distribution. Drug Distribution | E. Volume of Distribution 1. Distribution into the Water Compartments in the Body: b. Extracellular Fluid: If a drug has a low molecular weight but is hydrophilic, it can pass through the endothelial slit junctions of the capillaries into the interstitial fluid. However, hydrophilic drugs cannot move across the lipid membranes of cells to enter the intracellular fluid. Therefore, these drugs distribute into a volume that is the sum of the plasma volume and the interstitial fluid, which together constitute the extracellular fluid (about 20% of body weight or 14L in a 70-kg individual). Aminoglycoside antibiotics show this type of distribution. Drug Distribution | E. Volume of Distribution 1. Distribution into the Water Compartments in the Body: c. Total Body Water: If a drug has a low molecular weight and has enough lipophilicity, it can move into the interstitium through the slit junctions and pass through the cell membranes into the intracellular fluid. These drugs distribute into a volume of about 60% of body weight or about 42 L in a 70-kg individual. Ethanol exhibits this apparent Vd. Drug Distribution | E. Volume of Distribution 1. Distribution into the Water Compartments in the Body: c. Total Body Water: Note: In general, a larger Vd indicates greater distribution into tissues. A smaller Vd suggests confinement to plasma or extracellular fluid. Drug Distribution | E. Volume of Distribution 2. Determination of Vd : The fact that drug clearance is usually a first order process allows calculation of Vd. First order means that a constant fraction of the drug is eliminated per unit of time. This process can be most easily analyzed by plotting the log of the plasma drug concentration (Cp) versus time. The concentration of drug in the plasma can be extrapolated back to time zero (the time of IV bolus) on the Y axis to determine C0 , which is the concentration of drug that would have been achieved if the distribution phase had occurred instantly. Drug Distribution | E. Volume of Distribution 2. Determination of Vd : This allows calculation of Vd as: 𝐷𝑜𝑠𝑒 Vd = C0 For example, if 10 mg of drug is injected into a patient and the plasma concentration is extrapolated back to time zero, and C0 = 1 mg/L, then Vd = 10 mg/1 mg/L = 10 L. Drug Distribution | E. Volume of Distribution Figure – Drug concentrations in plasma after a single injection of drug at time = 0. A. B. Concentration data are plotted on a linear scale. B. Concentration data are plotted on a log scale. Drug Distribution | E. Volume of Distribution 3. Effect of Vd on drug half-life : Vd has an important influence on the half-life of a drug, because drug elimination depends on the amount of drug delivered to the liver or kidney (or other organs where metabolism occurs) per unit of time. Delivery of drug to the organs of elimination depends not only on blood flow but also on the fraction of drug in the plasma. If a drug has a large Vd most of the drug is in the extraplasmic space and is unavailable to the excretory organs. Therefore, any factor that increases Vd can increase the halflife and extend the duration of action of the drug. [Note: An exceptionally large Vd indicates considerable sequestration of the drug in some tissues or compartments.] Drug Clearance Through Metabolism Drug Clearance Through Metabolism Once a drug enters the body, the process of elimination begins. The three major routes of elimination are hepatic metabolism, biliary elimination, and urinary elimination. Together, these elimination processes decrease the plasma concentration exponentially. That is, a constant fraction of the drug present is eliminated in a given unit of time. Drug Clearance Through Metabolism Most drugs are eliminated according to first-order kinetics, although some, such as aspirin in high doses, are eliminated according to zero-order or nonlinear kinetics. Metabolism leads to production of products with increased polarity, which allows the drug to be eliminated. Clearance (CL) estimates the amount of drug cleared from the body per unit of time. The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal convoluted tubules. Therefore, lipid-soluble agents are first metabolized into more polar (hydrophilic) substances in the liver via two general sets of reactions, called phase I and phase II. Drug Clearance Through Metabolism Figure – The biotransformation of drugs Drug Clearance Through Metabolism Drug Clearance Through Kidney: Drugs must be sufficiently polar to be eliminated from the body. Removal of drugs from the body occurs via a number of routes, the most important being elimination through the kidney into the urine. Patients with renal dysfunction may be unable to excrete drugs and are at risk for drug accumulation and adverse effects. Elimination of drugs via the kidneys into urine involves the processes of glomerular filtration, active tubular secretion, and passive tubular reabsorption. Drug Clearance Through Metabolism Drug Clearance Through Kidney: 1. Glomerular Filtration: Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus. Free drug (not bound to albumin) flows through the capillary slits into the Bowman space as part of the glomerular filtrate. The glomerular filtration rate (GFR) is normally about 125 mL/min but may diminish significantly in renal disease. Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate. However, variations in GFR and protein binding of drugs do affect this process. Drug Clearance Through Metabolism Drug Clearance Through Kidney: 1. Glomerular Filtration: Drug Clearance Through Metabolism Drug Clearance Through Kidney: 2. Proximal Tubular Secretion: Drugs that were not transferred into the glomerular filtrate leave the glomeruli through efferent arterioles, which divide to form a capillary plexus surrounding the nephric lumen in the proximal tubule. Secretion primarily occurs in the proximal tubules by two energy-requiring active transport systems: one for anions (for example, deprotonated forms of weak acids) and one for cations (for example, protonated forms of weak bases). Each of these transport systems shows low specificity and can transport many compounds. Thus, competition between drugs for these carriers can occur within each transport system. Drug Clearance Through Metabolism Drug Clearance Through Kidney: 3. Distal Tubular Reabsorption: As a drug moves toward the distal convoluted tubule, its concentration increases and exceeds that of the perivascular space. The drug, if uncharged, may diffuse out of the nephric lumen, back into the systemic circulation. Manipulating the urine pH to increase the fraction of ionized drug in the lumen may be done to minimize the amount of back diffusion and increase the clearance of an undesirable drug. Drug Clearance Through Metabolism Drug Clearance Through Kidney: 3. Distal Tubular Reabsorption: As a general rule, weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine. This process is called “ion trapping.” For example, a patient presenting with phenobarbital (weak acid) overdose can be given bicarbonate, which alkalinizes the urine and keeps the drug ionized, thereby decreasing its reabsorption. Drug Clearance Through Metabolism Drug Clearance Through Kidney: Drug Clearance Through Metabolism Excretion by Other Routes: Drug excretion may also occur via the intestines, bile, lungs, and breast milk, among others. Drugs that are not absorbed after oral administration or drugs that are secreted directly into the intestines or into bile are excreted in the feces. The lungs are primarily involved in the elimination of anesthetic gases (for example, desflurane). Drug Clearance Through Metabolism Excretion by Other Routes: Elimination of drugs in breast milk may expose the breast-feeding infant to medications and/ or metabolites being taken by the mother and is a potential source of undesirable side effects to the infant. Excretion of most drugs into sweat, saliva, tears, hair, and skin occurs only to a small extent. Total body clearance and drug half-life are important measures of drug clearance that are used to optimize drug therapy and minimize toxicity. Drug Clearance Through Metabolism Excretion by Other Routes: A. Total Body Clearance: The total body (systemic) clearance, 𝐶𝑙𝑡𝑜𝑡𝑎𝑙 , is the sum of all clearances from the drug-metabolizing and drug-eliminating organs. The kidney is often the major organ of excretion. The liver also contributes to drug clearance through metabolism and/or excretion into the bile. Drug Clearance Through Metabolism Excretion by Other Routes: B. Clinical Situations Resulting in Changes in Drug Half-life: When a patient has an abnormality that alters the half-life of a drug, adjustment in dosage is required. Patients who may have an increase in drug half-life include those with: 1. Diminished renal or hepatic blood flow, for example, in cardiogenic shock, heart failure, or hemorrhage 2. Decreased ability to extract drug from plasma, for example, in renal disease 3. Decreased metabolism, for example, when a concomitant drug inhibits metabolism or in hepatic insufficiency, as with cirrhosis. Drug Clearance Through Metabolism Excretion by Other Routes: B. Clinical Situations Resulting in Changes in Drug Half-life: These patients may require a decrease in dosage or less frequent dosing intervals. In contrast, the half-life of a drug may be decreased by increased hepatic blood flow, decreased protein binding, or increased metabolism. This may necessitate higher doses or more frequent dosing intervals.