Pharmacokinetics and Pharmacodynamics

Overview

Pharmacokinetics and pharmacodynamics are fields of study that focus on the interplay between medications and the body.

Pharmacokinetics is the study of how the human body interacts with a drug:

• Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption
• Distribution
• Metabolism/ elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy

Pharmacodynamics is the study of the effects of a drug and its organ-specific mechanism of action, including effects on the cellular level:

• Drug-receptor binding dynamics
• Mechanism of action of the drug
• Physiologic response

Pharmacokinetics: Absorption

Definition

Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption is the transfer of a drug or substance from the site of administration to the bloodstream and is determined by:

• The drug’s physicochemical properties:
  • Lipid solubility 
  • Particle size 
  • Degree of ionization
• Drug formulation
• Route of administration
  • Oral
  • IV
  • IM

Oral administration

Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption through the GI tract is affected by:

• Differences in luminal pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance along the GI tract:
  • Most drugs are weak organic acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance or bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance. 
  • Drugs exist in un-ionized and ionized forms.
  • The un-ionized form is usually lipid-soluble (lipophilic) and diffuses readily across cell membranes.
  • The ionized form has high water solubility ( hydrophilic Hydrophilic Aminoglycosides).
  • The proportion of the un-ionized form is determined by:
    • The environmental pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance  
    • The drug’s pKa (acid dissociation Dissociation Defense Mechanisms constant): the pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance at which concentrations of ionized and un-ionized forms are equal 
• Surface area per luminal volume:
  • The small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy has the largest surface area.
  • Most absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption occurs in the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy.
• Blood perfusion of the absorptive membrane:
  • Decreased blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure (e.g., in shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock) reduces absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption.
• Presence of bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy and mucus:
  • In the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy, a thick mucous layer limits drug absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption.
• Chemical reactions:
  • Hydrolysis Hydrolysis The process of cleaving a chemical compound by the addition of a molecule of water. Proteins and Peptides by gastric acid Gastric acid Hydrochloric acid present in gastric juice. Gastroesophageal Reflux Disease (GERD) or digestive enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
  • Metabolism by bacterial flora of the GI tract
• Transit time:
  • Rapid transit (e.g., diarrheal states) through the GI tract will hinder absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption.
  • Delayed gastric emptying Gastric emptying The evacuation of food from the stomach into the duodenum. Gastrointestinal Motility will impair absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption by the small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy.
• The nature of epithelial membranes (see below)

Drugs will cross membranes through:

• Passive diffusion, depending on:
  • Degree of concentration gradient across membrane: Drugs move from high- to low-concentration areas.
  • Drug’s lipid solubility: Because membranes are lipid, lipid-soluble drugs diffuse more rapidly.
  • Drug particle size: Small particles penetrate membranes more rapidly.
  • Degree of ionization: because it determines lipid solubility
  • Area of absorptive surface: the larger the surface the more the diffusion Diffusion The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space. Diffusion, especially facilitated diffusion, is a major mechanism of biological transport. Peritoneal Dialysis and Hemodialysis
  • Fick’s law governs passive diffusion Diffusion The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space. Diffusion, especially facilitated diffusion, is a major mechanism of biological transport. Peritoneal Dialysis and Hemodialysis, showing that the diffusion Diffusion The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space. Diffusion, especially facilitated diffusion, is a major mechanism of biological transport. Peritoneal Dialysis and Hemodialysis rate is proportional to:

D: diffusion Diffusion The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space. Diffusion, especially facilitated diffusion, is a major mechanism of biological transport. Peritoneal Dialysis and Hemodialysis constant for the drug
A: surface area of the membrane
T: thickness of the membrane
C: concentration gradient

• Facilitated passive diffusion Diffusion The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space. Diffusion, especially facilitated diffusion, is a major mechanism of biological transport. Peritoneal Dialysis and Hemodialysis:
  • Requires presence of a carrier Carrier Vaccination molecule that binds the drug and carries it across the membrane
  • The diffusion Diffusion The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space. Diffusion, especially facilitated diffusion, is a major mechanism of biological transport. Peritoneal Dialysis and Hemodialysis still occurs along a concentration gradient.
  • Does not require energy expenditure Energy expenditure Energy expenditure is the sum of internal heat produced and external work. Energy Homeostasis
• Active transport Active transport The movement of materials across cell membranes and epithelial layers against an electrochemical gradient, requiring the expenditure of metabolic energy. The Cell: Cell Membrane:
  • Requires energy expenditure Energy expenditure Energy expenditure is the sum of internal heat produced and external work. Energy Homeostasis
  • May occur against a concentration gradient
  • Occurs with drugs that are similar to endogenous substances—i.e., vitamins, sugars, amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids
• Pinocytosis:
  • Fluid or particles are engulfed by the cell in the form of vesicles Vesicles Female Genitourinary Examination
  • Requires energy expenditure Energy expenditure Energy expenditure is the sum of internal heat produced and external work. Energy Homeostasis

Bioavailability

• The extent and rate at which a drug enters systemic circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment, thereby accessing the site of action
• Relevant only for orally administered drugs, as IV drugs have 100% bioavailability
• Factors that affect bioavailability:
  • Anything affecting absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption 
  • Hepatic 1st-pass metabolism
    • Drugs absorbed in the GI tract go through the portal circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment and end up in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy.
    • The liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy metabolizes the drug before it enters systemic circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment, reducing the drug’s bioavailability. 
  • Enterohepatic circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment:
    • Drug is absorbed in the GI tract and, through portal circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment, is taken up by the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy.
    • The active drug or its metabolites are excreted in the bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy and then into the intestine. 
    • The gut microbiota deconjugate drug metabolites to release the parent drug molecule. 
    • The drug is then reabsorbed in the intestine → cycle restarts 
    • Recirculation may produce multiple peaks in the drug’s plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products concentration.

Pharmacokinetics: Distribution

Definition

Distribution is the extent to which a drug is transported from the systemic circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment to target tissues and organs.

Volume of distribution (Vd)

• The volume necessary to contain the total amount of a drug at the same concentration in which it is observed in plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products
• Can also be conceptualized as the ratio of the amount of drug in a body (dose) to concentration of the drug measured in blood and plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products and unbound in interstitial fluid Interstitial fluid Body Fluid Compartments
• A theoretical volume that provides a reference for the plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products concentration expected for a given dose

The equation for the volume of distribution:

Factors that affect drug distribution

• Tissue permeability of drugs; depends on a drug’s:
  • Molecular size: Smaller molecules distribute to a larger degree into tissues.
  • pKa: determines degree of ionization and thus lipophilicity:
    • Lipophilic drugs dissolve in lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids: lipid diffusion Diffusion The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space. Diffusion, especially facilitated diffusion, is a major mechanism of biological transport. Peritoneal Dialysis and Hemodialysis
    • Lipophilic drugs can cross lipid cell membranes.
    • Lipophilic drugs can cross the blood– brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification and placental barriers.
    • Hydrophilic Hydrophilic Aminoglycosides drugs dissolve in water: aqueous diffusion Diffusion The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space. Diffusion, especially facilitated diffusion, is a major mechanism of biological transport. Peritoneal Dialysis and Hemodialysis
    • Hydrophilic Hydrophilic Aminoglycosides drugs require pores or transporters to cross membranes.
• Tissue barriers:
  • Blood–brain barrier Blood–Brain Barrier Meningitis in Children: In brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries: Histology, endothelial cells are connected with tight intercellular junctions Intercellular junctions Direct contact of a cell with a neighboring cell. Most such junctions are too small to be resolved by light microscopy, but they can be visualized by conventional or freeze-fracture electron microscopy, both of which show that the interacting cell membrane and often the underlying cytoplasm and the intervening extracellular space are highly specialized in these regions. Surface Epithelium: Histology.
  • Placental barrier Placental barrier The placental barrier is a selectively permeable membrane separating the maternal and fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity: formed by fetal trophoblastic basement membrane Basement membrane A darkly stained mat-like extracellular matrix (ecm) that separates cell layers, such as epithelium from endothelium or a layer of connective tissue. The ecm layer that supports an overlying epithelium or endothelium is called basal lamina. Basement membrane (bm) can be formed by the fusion of either two adjacent basal laminae or a basal lamina with an adjacent reticular lamina of connective tissue. Bm, composed mainly of type IV collagen; glycoprotein laminin; and proteoglycan, provides barriers as well as channels between interacting cell layers. Thin Basement Membrane Nephropathy (TBMN) and an endothelial layer
  • Blood–testis barrier: formed by tight junctions Tight junctions Cell-cell junctions that seal adjacent epithelial cells together, preventing the passage of most dissolved molecules from one side of the epithelial sheet to the other. The Cell: Cell Junctions between Sertoli testicular cells
• Cardiac output Cardiac output The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). Cardiac Mechanics/regional blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure:
  • The higher the organ blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure, the greater the drug distribution
  • The larger the organ, the higher the blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure to it
• Degree of protein binding:
  • Albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests is the main drug-binding protein in plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products.
  • Other binding proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis are alpha-1 acid glycoprotein and lipoproteins Lipoproteins Lipid-protein complexes involved in the transportation and metabolism of lipids in the body. They are spherical particles consisting of a hydrophobic core of triglycerides and cholesterol esters surrounded by a layer of hydrophilic free cholesterol; phospholipids; and apolipoproteins. Lipoproteins are classified by their varying buoyant density and sizes. Lipid Metabolism.
  • Only unbound drug can passively diffuse to extravascular or tissue sites to exert its effects.
  • The unbound drug concentration in plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products determines drug concentration at the active site Active site Area of an enzyme that binds to specific substrate molecules in order to facilitate a reaction. Basics of Enzymes and efficacy.
  • Albumin-bound drugs remain intravascular.
  • High protein binding decreases volume of distribution, as drugs cannot diffuse into tissues.
  • Unbound drugs can diffuse and bind BIND Hyperbilirubinemia of the Newborn to tissues and have a large volume of distribution.
• Body composition:
  • Extracellular water: affects volume of distribution of hydrophilic Hydrophilic Aminoglycosides drugs
  • Adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or “brite” adipose tissue, which is a transitional form. Adipose Tissue: Histology: affects volume of distribution of lipophilic drugs
• Age:
  • Total body water Total body water Body Fluid Compartments is higher in infants.
  • Fat content is higher in infants and elderly.
  • Skeletal muscle is lower in infants and elderly.
  • Organ composition: immature nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. Nervous System: Anatomy, Structure, and Classification in infants → greater distribution of drugs into brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification
  • Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products protein content is lower in infants and elderly.
• Sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria:
  • Women have less total body water Total body water Body Fluid Compartments, owing to smaller size, and more fat tissue.
• Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care:
  • Increased blood volume leads to greater Vd.
  • The fetus is a separate compartment in which drugs can distribute.
• Obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity:
  • High adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or “brite” adipose tissue, which is a transitional form. Adipose Tissue: Histology leads to higher distribution and accumulation of lipophilic drugs.
• Disease states can affect:
  • Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests concentrations
  • Tissue perfusion: i.e., hypoperfusion in shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock
  • Tissue pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance: i.e., lactic acidosis Lactic Acidosis Oxazolidinones due to sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock
  • Alteration in physiologic barriers: Meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis alters the blood–brain barrier Blood–Brain Barrier Meningitis in Children.
• Diet:
  • A diet high in fats Fats The glyceryl esters of a fatty acid, or of a mixture of fatty acids. They are generally odorless, colorless, and tasteless if pure, but they may be flavored according to origin. Fats are insoluble in water, soluble in most organic solvents. They occur in animal and vegetable tissue and are generally obtained by boiling or by extraction under pressure. They are important in the diet (dietary fats) as a source of energy. Energy Homeostasis increases free fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance, which compete with drugs for binding to albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests.
  • Malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries decreases plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests levels, affecting drug binding and tissue distribution.
• Drug interactions:
  • Displacement Displacement The process by which an emotional or behavioral response that is appropriate for one situation appears in another situation for which it is inappropriate. Defense Mechanisms occurs when 2 drugs that have the same affinity for the same binding site are administered concomitantly.

Pharmacokinetics: Metabolism

Biotransformation

Biotransformation is the process through which the human body chemically changes drugs into different molecules to either make the compound pharmacologically active or to facilitate elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy. 

• Metabolism is a type of biotransformation.
• Usually takes place in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy, through hepatic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
• When a drug or parent compound is metabolized, it can be converted into:
  • Inactive form 
  • Pharmacologically active form
  • Toxic metabolite

Phases of biotransformation

• Phase I reactions: change the drug into a polar metabolite, which makes it more water-soluble
  • This is done by either unmasking or inserting a polar group (–OH, –SH, –NH₂).
  • Performed by cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-Induced Liver Injury (CYP450) isoenzymes Isoenzymes Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics. Basics of Enzymes in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy
  • 75% of drugs are metabolized by CYP450-3A4, CYP450-3A5, and CYP450-2D6.
• Phase II reactions: conjugation Conjugation A parasexual process in bacteria; algae; fungi; and ciliate eukaryota for achieving exchange of chromosome material during fusion of two cells. In bacteria, this is a unidirectional transfer of genetic material; in protozoa it is a bi-directional exchange. In algae and fungi, it is a form of sexual reproduction, with the union of male and female gametes. Bacteriology of the metabolite with compounds to increase water solubility, including:
  • Glucuronidation 
  • Acetylation Acetylation Formation of an acetyl derivative. Chloramphenicol
  • Glutathione conjugation Conjugation A parasexual process in bacteria; algae; fungi; and ciliate eukaryota for achieving exchange of chromosome material during fusion of two cells. In bacteria, this is a unidirectional transfer of genetic material; in protozoa it is a bi-directional exchange. In algae and fungi, it is a form of sexual reproduction, with the union of male and female gametes. Bacteriology
  • Sulfation
  • Methylation Methylation Addition of methyl groups. In histo-chemistry methylation is used to esterify carboxyl groups and remove sulfate groups by treating tissue sections with hot methanol in the presence of hydrochloric acid. . Glucocorticoids
• Phase III reactions: further processing of the drugs, including:
  • Preparation of a drug for excretion into the bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy, urine, or other lumens
  • Binding to transport proteins Transport proteins Proteins and Peptides, usually P-glycoproteins
• Not all drugs undergo all 3 phases.
• There is great genetic variability in the activity of enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes involved in all 3 phases.
• As a result, individuals may exhibit significant differences in their ability to metabolize the same drug.
• A great number of medications can induce and inhibit the P450 enzyme system.

Factors affecting drug metabolism

• Genetic differences of CYP450
• Competitive inhibition Competitive inhibition Enzyme Inhibition of CYP450:
  • Drugs may compete for the same pathway.
  • A drug may inhibit or induce the metabolism of another drug.
• Direct inhibition of CYP450:
  • Amiodarone Amiodarone An antianginal and class III antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting potassium channels and voltage-gated sodium channels. There is a resulting decrease in heart rate and in vascular resistance. Pulmonary Fibrosis, ritonavir Ritonavir An HIV protease inhibitor that works by interfering with the reproductive cycle of HIV. It also inhibits cytochrome p-450 cyp3a. Anti-HIV Drugs, cimetidine Cimetidine A histamine congener, it competitively inhibits histamine binding to histamine h2 receptors. Cimetidine has a range of pharmacological actions. It inhibits gastric acid secretion, as well as pepsin and gastrin output. Antihistamines, grapefruit juice, fluconazole Fluconazole Triazole antifungal agent that is used to treat oropharyngeal candidiasis and cryptococcal meningitis in aids. Azoles
  • Suicide inhibitors Suicide inhibitors Enzyme Inhibition: irreversible enzyme/ receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors inhibition, e.g., secobarbital
• Induction of CYP450:
  • Antiseizure medications, ethanol Ethanol A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. Ethanol Metabolism, St. John’s Wort, rifampin Rifampin A semisynthetic antibiotic produced from streptomyces mediterranei. It has a broad antibacterial spectrum, including activity against several forms of Mycobacterium. In susceptible organisms it inhibits dna-dependent RNA polymerase activity by forming a stable complex with the enzyme. It thus suppresses the initiation of RNA synthesis. Rifampin is bactericidal, and acts on both intracellular and extracellular organisms. Epiglottitis
• Inhibition of P-glycoprotein ( multidrug resistant Multidrug resistant Resistant to at least 1 agent in > 3 antibiotic categories Pseudomonas mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations (MDR1))
  • Moves drugs from inside the cell to the intestinal lumen
  • Inhibiting MDR1 increases drug intracellular levels, leading to toxicity Toxicity Dosage Calculation
  • Inhibitors include verapamil Verapamil A calcium channel blocker that is a class IV anti-arrhythmia agent. Pulmonary Hypertension Drugs and grapefruit juice.
  • Medications metabolized by MDR1 include cyclosporine Cyclosporine A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. Immunosuppressants and digoxin Digoxin A cardiotonic glycoside obtained mainly from digitalis lanata; it consists of three sugars and the aglycone digoxigenin. Digoxin has positive inotropic and negative chronotropic activity. It is used to control ventricular rate in atrial fibrillation and in the management of congestive heart failure with atrial fibrillation. Its use in congestive heart failure and sinus rhythm is less certain. The margin between toxic and therapeutic doses is small. Cardiac Glycosides
• Amount of blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure to the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy

Rate of metabolism

• 1st-order kinetics:
  • At therapeutic concentrations, only a small fraction of the metabolizing enzyme’s sites are occupied by the drug.
  • The metabolism rate increases with drug concentration.
  • The metabolism rate of the drug is a constant fraction of the drug remaining in the body.
  • The drug has a specific half-life: time needed for the plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products concentration to reduce to half its original value.
• Zero-order kinetics:
  • Most of the metabolizing enzyme drug-binding sites are occupied.
  • Metabolism occurs at its maximal rate and does not change in proportion to drug concentration.
  • In this case, no specific half-life can be determined.
  • As drug concentration increases, metabolism shifts from 1st-order to zero-order kinetics.

Mnemonics for CYP450 inducers and inhibitors

• Inducers: PARC GPS
  • Phenytoin
  • Alcohol ( ethanol Ethanol A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. Ethanol Metabolism)
  • Rifampin
  • Carbamazepine
  • Griseofulvin
  • Phenobarbital
  • Smoking
  • St. John’s wort
• Inhibitors: PACMAN-G
  • Protease inhibitors
  • Azole antifungals
  • Cimetidine 
  • Macrolides
  • Amiodarone
  • Nondihydropyridine (non-DHP) calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes channel blockers ( CCBs CCBs Calcium channel blockers (CCBS) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBS: dihydropyridines and non-dihydropyridines. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers))
  • Grapefruit juice

Pharmacodynamics: Drug Receptors and Effectors

Receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors are macromolecules involved in chemical signaling between and within cells. 

• These receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors may be located on the cell surface membrane or within the cytoplasm:
  • Cell surface receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors have a transmembrane part that connects them to the cytoplasm:
    • G-protein–coupled receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
    • Tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
    • Ion channels Channels The Cell: Cell Membrane
  • Intracellular receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (e.g., steroid receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors): The drug or ligand must be lipophilic.
    • Steroid receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
    • Thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy hormone receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
    • Vitamin A Vitamin A Retinol and derivatives of retinol that play an essential role in metabolic functioning of the retina, the growth of and differentiation of epithelial tissue, the growth of bone, reproduction, and the immune response. Dietary vitamin A is derived from a variety of carotenoids found in plants. It is enriched in the liver, egg yolks, and the fat component of dairy products. Fat-soluble Vitamins and their Deficiencies and D receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
• A drug can bind BIND Hyperbilirubinemia of the Newborn a specific molecular region of the receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors called the recognition site.
  • The recognition site of a drug may be different from that of another drug binding to the same receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors.
• A drug binding to a receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors can activate or deactivate it, leading to increased or decreased function:
  • Agonists activate receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors to produce the desired response.
  • Antagonists prevent receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors activation:
    • Can be reversible or irreversible ( suicide Suicide Suicide is one of the leading causes of death worldwide. Patients with chronic medical conditions or psychiatric disorders are at increased risk of suicidal ideation, attempt, and/or completion. The patient assessment of suicide risk is very important as it may help to prevent a serious suicide attempt, which may result in death. Suicide antagonists)
    • Competitive antagonists prevent binding of the agonist to the receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors.
    • Noncompetitive antagonists allow binding of the agonist to the receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors but reduce or prevent its effect.
• A drug’s ability to affect a given receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors is related to its:
  • Affinity: probability Probability Probability is a mathematical tool used to study randomness and provide predictions about the likelihood of something happening. There are several basic rules of probability that can be used to help determine the probability of multiple events happening together, separately, or sequentially. Basics of Probability of the drug occupying a receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors at any given instant
    • A drug’s affinity and activity are determined by its chemical structure.
    • A drug’s affinity for the receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors determines the amount of drug needed to produce a therapeutic effect.
  • Intrinsic efficacy: degree to which a ligand activates receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors and leads to cellular response
• The duration of time that the drug– receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors complex persists determines the pharmacologic effect :
  • Transient occupancy of the receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors produces the desired pharmacologic effect
• Receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors up- and down-regulation: Receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors density is proportional to receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors binding.
  • Low drug concentration leads to up-regulation of receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors 
  • High drug concentration leads to down-regulation of receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors 
• Tolerance: reduced drug effect over time due to changes in number and function of receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
• 2nd messengers: intracellular molecules activated in response to drug– receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors interaction. Example:
  • Drug ( epinephrine Epinephrine The active sympathomimetic hormone from the adrenal medulla. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. Sympathomimetic Drugs) binds to the receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors G-protein.
  • The receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors makes a change in the G-protein.
  • G-proteins dissociate and bind BIND Hyperbilirubinemia of the Newborn to the effector (adenylyl cyclase).
  • The effector catalyzes a reaction that increases the concentration of the 2nd messenger ( cAMP cAMP An adenine nucleotide containing one phosphate group which is esterified to both the 3′- and 5′-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and acth. Phosphodiesterase Inhibitors)
  • cAMP cAMP An adenine nucleotide containing one phosphate group which is esterified to both the 3′- and 5′-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and acth. Phosphodiesterase Inhibitors increases heart rate Heart rate The number of times the heart ventricles contract per unit of time, usually per minute. Cardiac Physiology, dilation of skeletal muscle blood vessels, and breakdown of glycogen to glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance.

Pharmacodynamics: Drug Effect

The effect of a drug is the physical response it elicits. This may be a desired (therapeutic) effect or an undesired (toxic) effect. The effect can be modulated by the presence of antagonists and is also determined by its affinity to its target molecular receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors. These effects are measured and can be visually represented through curves.

Dose–response curves

• Graphical representations of the relationship between the dosage Dosage Dosage Calculation of a drug given and the amount of effect it produces
• The dose of drug is plotted on the x-axis and the maximal % response on the y-axis.
• Expressed as a sigmoid-shaped log curve
• E_max: drug dose or concentration that elicits a maximal effect (response)
• ED₅₀: drug dose or concentration (EC₅₀)  that produces 50% maximal effect (response) 
• Slope of the curve gives the change in effect per unit of drug concentration increased
• When viewing a dose–response curve:
  • Agonist alone achieves 100% effect 
  • Addition of competitive antagonist: a higher agonist dose is needed to still achieve 100% effect  →  curve shifts right
  • Addition of noncompetitive inhibitor: a higher agonist dose will not achieve 100% effect and maximal effect achievable of agonist is reduced → curve does not shift

Binding curves

• Express the concentration of a drug needed to saturate a specific receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
• Dose of the drug on the x-axis, and maximal % of bound receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors on the y-axis
• Expressed as a sigmoid-shaped log curve
• K_d ( dissociation Dissociation Defense Mechanisms constant):
  • Defined as the drug concentration that results in 50% of receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors being bound 
  • Lower K_d → higher binding affinity of drug for receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
  • Higher K_d → weaker binding affinity of the drug for receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
  • Maximal biologic response (B_max) does not always require full receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors occupancy by drug
  • Sometimes ED₅₀ is achieved at a drug concentration less than K_d; this is due to the presence of “spare” receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors.
  • Spare receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors differ based on drug, organ, and species.

Quantal curves

• In a population, there is usually some variation of doses required to achieve the defined drug effect
• A quantal dose response describes a defined drug effect that is either present or absent
• Dose of a drug on the x-axis, and % responders on the y-axis for a population
• The cumulative percentage of the population responses to increasing doses is plotted as a sigmoid Sigmoid A segment of the colon between the rectum and the descending colon. Volvulus shape
• E₅₀ : drug dose that elicits the defined drug effect in 50% of subjects

Toxicity Toxicity Dosage Calculation curves and therapeutic ratios

• Illustrates dosing range between minimum effective and minimum toxic concentrations
• A graph containing 2 curves:
  • The curve relating dose to efficacy (dose–response curve)
  • The curve relating dose to toxicity Toxicity Dosage Calculation (kill–response curve)
  • Therapeutic window Therapeutic Window Dosage Calculation: range between the minimum therapeutic dose and minimum toxic dose
  • ED₅₀: dose for the desired effect in 50% of population 
  • TD₅₀: dose for a toxic effect in 50% of population 
  • Therapeutic index Therapeutic Index An indicator of the benefits and risks of treatment. Dosage Calculation (TI): TD₅₀/ED₅₀ 
  • The higher the TI, the safer the drug

Potency curves

• Potency is determined by the affinity of a drug for its receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors:
  • The greater the affinity, the higher the potency 
• Potency curves consist of dose–response curves of different drugs for comparison.  
• Potency is the concentration (EC₅₀) or dose (ED₅₀) of a drug that produces 50% of the maximal effect.
• The higher a drug’s potency, the lower its EC₅₀ (or ED₅₀)
  • Example: A drug with an ED₅₀ of 5 mg is 10x more potent than a drug whose ED₅₀ is 50 mg.

Elimination and Excretion

Rate of elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy

Elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy is the process of conversion of a drug to inactive metabolites, which are ultimately excreted from the body.

• Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy (hepatic): primary organ for metabolic elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy of drugs
• Kidney (renal): primary organ for excretory elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy of drugs

Rate of elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy of drug ( mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast/time) = clearance x concentration.

Clearance

• Volume of plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cleared of drug per unit time (volume/time) 
• Total systemic clearance (CL_total):
  • A drug can be cleared through many pathways and organs.
  • CL_total is the sum of all relevant clearances.
  • CL_total = CL_hepatic + CL_renal + CL_pulmonary + CL_other

Renal clearance

General:

• Measured by glomerular filtration rate Glomerular filtration rate The volume of water filtered out of plasma through glomerular capillary walls into Bowman’s capsules per unit of time. It is considered to be equivalent to inulin clearance. Kidney Function Tests ( GFR GFR The volume of water filtered out of plasma through glomerular capillary walls into Bowman’s capsules per unit of time. It is considered to be equivalent to inulin clearance. Kidney Function Tests) 
• Determined by the drug’s plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products concentration and whether it undergoes active secretion Secretion Coagulation Studies or reabsorption in the kidney 
• Drugs cannot passively diffuse from the blood across the glomerular membrane if they:
  • Are bound to protein 
  • Have a molecular weight > 60,000 daltons 
• Some drugs are actively secreted from the blood into the proximal tubules.
• Many drugs are passively reabsorbed back into the blood at the distal tubules.  

Calculating renal clearance:

• GFR GFR The volume of water filtered out of plasma through glomerular capillary walls into Bowman’s capsules per unit of time. It is considered to be equivalent to inulin clearance. Kidney Function Tests can be calculated:
  • GFR GFR The volume of water filtered out of plasma through glomerular capillary walls into Bowman’s capsules per unit of time. It is considered to be equivalent to inulin clearance. Kidney Function Tests equations offer guidance on dosing of renally cleared drugs.
  • Measures the urinary clearance of an endogenous filtration marker 
• Serum creatinine is the most frequently used endogenous filtration marker.
  • Creatinine clearance Creatinine clearance Kidney Function Tests is used to approximate GFR GFR The volume of water filtered out of plasma through glomerular capillary walls into Bowman’s capsules per unit of time. It is considered to be equivalent to inulin clearance. Kidney Function Tests and measure kidney function.
  • Creatinine clearance Creatinine clearance Kidney Function Tests is the volume of plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cleared of creatinine per unit of time.
  • Creatinine is a by-product of normal muscle breakdown and protein-rich foods.
  • Serum creatinine levels vary by age, weight, sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria, and muscle mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast.
• Creatinine-based renal clearance equations:
  • Cockcroft-Gault: uses 3 variables (age, serum creatinine, weight)
  • Modification of diet in renal disease (MDRD): uses 4 variables (age, race, serum creatinine, sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria) 
  • Chronic kidney disease-epidemiology (CKD-EPI): uses age, race, serum creatinine, sex Sex The totality of characteristics of reproductive structure, functions, phenotype, and genotype, differentiating the male from the female organism. Gender Dysphoria 
  • Equations can overestimate GFR GFR The volume of water filtered out of plasma through glomerular capillary walls into Bowman’s capsules per unit of time. It is considered to be equivalent to inulin clearance. Kidney Function Tests because creatinine undergoes tubular secretion Secretion Coagulation Studies.
• When not to use creatinine-based renal clearance equations:
  • Unstable creatinine concentrations
  • Extremes in muscle mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast (bodybuilders) or diet ( anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa)
  • In individuals who are paraplegic or otherwise immobile
  • Muscle wasting Muscle Wasting Duchenne Muscular Dystrophy diseases (e.g., Duchenne muscular dystrophy Muscular Dystrophy Becker Muscular Dystrophy)
  • Vegetarian or low-meat diet
  • Creatine Creatine An amino acid that occurs in vertebrate tissues and in urine. In muscle tissue, creatine generally occurs as phosphocreatine. Creatine is excreted as creatinine in the urine. Acute Kidney Injury dietary supplements
  • Extremes of age 
• Cystatin C Cystatin C An extracellular cystatin subtype that is abundantly expressed in bodily fluids. It may play a role in the inhibition of interstitial cysteine proteases. Kidney Function Tests–based renal clearance equations:
  • More accurate endogenous renal filtration marker than creatinine
  • Cystatin C Cystatin C An extracellular cystatin subtype that is abundantly expressed in bodily fluids. It may play a role in the inhibition of interstitial cysteine proteases. Kidney Function Tests is a protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS inhibitor produced by all nucleated cells.
  • Undergoes filtration, but not secretion Secretion Coagulation Studies or reabsorption 
  • CKD-EPI cystatin C Cystatin C An extracellular cystatin subtype that is abundantly expressed in bodily fluids. It may play a role in the inhibition of interstitial cysteine proteases. Kidney Function Tests equation is used to measure renal clearance in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with low muscle mass Mass Three-dimensional lesion that occupies a space within the breast Imaging of the Breast.

Biliary excretion

• Some drugs are extensively excreted in the bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy.
• These drugs undergo active transport Active transport The movement of materials across cell membranes and epithelial layers against an electrochemical gradient, requiring the expenditure of metabolic energy. The Cell: Cell Membrane against a concentration gradient.
• Drugs are more likely to be excreted in bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy if:
  • They have high molecular weight
  • They contain polar and lipophilic groups
• Conjugation Conjugation A parasexual process in bacteria; algae; fungi; and ciliate eukaryota for achieving exchange of chromosome material during fusion of two cells. In bacteria, this is a unidirectional transfer of genetic material; in protozoa it is a bi-directional exchange. In algae and fungi, it is a form of sexual reproduction, with the union of male and female gametes. Bacteriology with glucuronic acid facilitates biliary excretion.
• The enterohepatic cycle limits biliary excretion of drugs.

Elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy kinetics

• Half-life (T_1/2): time (in minutes or hours) required for the plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products concentration of a drug to decrease by 50% after the completion of drug absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption and distribution:
  • In other words, the amount of time it takes to eliminate half the drug
  • Typically, 5 half-lives are required to fully eliminate a drug 
  • Steady-state: concentration of drug absorbed equals the concentration of drug eliminated
• 1st-order kinetics:
  • A constant percentage or fraction of drug is eliminated per unit of time.
  • The elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy is directly proportional to the concentration of the drug.
  • Also referred to as linear or nonsaturable kinetics
• Zero-order kinetics:
  • A constant quantity of drug is eliminated per unit of time
  • The elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy is independent of the concentration of the drug
  • Also known as saturable, nonlinear, or concentration-independent kinetics