Pharmacokinetics and Pharmacodynamics

Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Another way to describe the difference between the 2 disciplines is to say that pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.” When prescribing medications, physicians must take into account both the drug’s pharmacodynamics and its pharmacokinetics to determine the correct dosage and to ensure the appropriate effect.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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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

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 and pharmacodynamics

Pharmacokinetics and pharmacodynamics

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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 along the GI tract:
    • Most drugs are weak organic acids or bases. 
    • 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).
    • The proportion of the un-ionized form is determined by:
      • The environmental pH  
      • The drug’s pKa (acid dissociation constant): the pH 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 has the largest surface area.
    • Most 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.
  • Blood perfusion of the absorptive membrane: 
    • Decreased blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. 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.
  • Presence of bile 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, a thick mucous layer limits drug absorption.
  • Chemical reactions: 
    • Hydrolysis by gastric acid 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.
    • Delayed gastric emptying will impair 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.
  • 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
    • Fick’s law governs passive diffusion, showing that the diffusion rate is proportional to:
$$ V_{liquid}= D \frac{A}{T}(C_{1}-C_{2}) $$

D: diffusion constant for the drug
A: surface area of the membrane
T: thickness of the membrane
C: concentration gradient

  • Facilitated passive diffusion:
    • Requires presence of a carrier molecule that binds the drug and carries it across the membrane
    • The diffusion still occurs along a concentration gradient.
    • Does not require energy expenditure
  • 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
    • May occur against a concentration gradient
    • Occurs with drugs that are similar to endogenous substances—i.e., vitamins, sugars, amino acids
  • Pinocytosis:
    • Fluid or particles are engulfed by the cell in the form of vesicles
    • Requires energy expenditure

Bioavailability

  • The extent and rate at which a drug enters systemic circulation Systemic circulation Circulation is the movement of blood throughout the body through one continuous circuit of blood vessels. Different organs have unique functions and, therefore, have different requirements, circulatory patterns, and regulatory mechanisms. Systemic and Special Circulations, 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 
    • Hepatic 1st-pass metabolism 
      • Drugs absorbed in the GI tract go through the portal circulation 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.
      • 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 metabolizes the drug before it enters systemic circulation Systemic circulation Circulation is the movement of blood throughout the body through one continuous circuit of blood vessels. Different organs have unique functions and, therefore, have different requirements, circulatory patterns, and regulatory mechanisms. Systemic and Special Circulations, reducing the drug’s bioavailability. 
    • Enterohepatic circulation: 
      • Drug is absorbed in the GI tract and, through portal circulation, 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.
      • The active drug or its metabolites are excreted in the bile 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 concentration.
Drug undergoing the first-pass metabolism

Phenomenon of a drug undergoing 1st-pass metabolism, during which it is partially or completely metabolized in the intestinal wall or is absorbed in the intestine and enters the portal circulation and travels 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, where the drug is metabolized further.

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Pharmacokinetics: Distribution

Definition

Distribution is the extent to which a drug is transported from the systemic circulation Systemic circulation Circulation is the movement of blood throughout the body through one continuous circuit of blood vessels. Different organs have unique functions and, therefore, have different requirements, circulatory patterns, and regulatory mechanisms. Systemic and Special Circulations 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
  • 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 and unbound in interstitial fluid
  • A theoretical volume that provides a reference for the plasma concentration expected for a given dose

The equation for the volume of distribution:

$$ V_{d}= \frac{Amount\ of\ drug\ in\ the\ body}{Concentration\ in\ the\ blood} $$

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
      • Lipophilic drugs can cross lipid cell membranes.
      • Lipophilic drugs can cross the blood–brain and placental barriers.
      • Hydrophilic drugs dissolve in water: aqueous diffusion
      • Hydrophilic drugs require pores or transporters to cross membranes.
  • Tissue barriers:
    • Blood–brain barrier: In brain 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, endothelial cells are connected with tight intercellular junctions.
    • Placental barrier: formed by fetal trophoblastic basement membrane and an endothelial layer
    • Blood–testis barrier: formed by tight junctions between Sertoli testicular cells
  • Cardiac output/regional blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure:
    • The higher the organ blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure, the greater the drug distribution
    • The larger the organ, the higher the blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure to it
  • Degree of protein binding:
    • Albumin is the main drug-binding protein in plasma.
    • Other binding proteins are alpha-1 acid glycoprotein and lipoproteins.
    • Only unbound drug can passively diffuse to extravascular or tissue sites to exert its effects.
    • The unbound drug concentration in plasma determines drug concentration at the active site 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 to tissues and have a large volume of distribution.
  • Body composition:
    • Extracellular water: affects volume of distribution of hydrophilic 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: affects volume of distribution of lipophilic drugs
  • Age:
    • Total body water 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. General Structure of the Nervous System in infants → greater distribution of drugs into brain
    • Plasma protein content is lower in infants and elderly.
  • Sex: 
    • Women have less total body water, owing to smaller size, and more fat tissue.
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine 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 leads to higher distribution and accumulation of lipophilic drugs.
  • Disease states can affect:
    • Plasma albumin 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: i.e., lactic acidosis due to sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. 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.
  • Diet:
    • A diet high in fats increases free fatty acids Fatty acids Fatty acids are integral building blocks of lipids, and can be classified as unsaturated or saturated based on the presence/absence of carbon-carbon double bonds within their nonpolar chains. Fatty Acids and Lipids, which compete with drugs for binding to albumin.
    • 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 albumin levels, affecting drug binding and tissue distribution.
  • Drug interactions:
    • Displacement 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. 

  • 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, 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 (CYP450) isoenzymes 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
    • 75% of drugs are metabolized by CYP450-3A4, CYP450-3A5, and CYP450-2D6.
  • Phase II reactions: conjugation of the metabolite with compounds to increase water solubility, including:
    • Glucuronidation 
    • Acetylation
    • Glutathione conjugation
    • Sulfation
    • Methylation
  • Phase III reactions: further processing of the drugs, including: 
    • Preparation of a drug for excretion into the bile, urine, or other lumens
    • Binding to transport proteins, 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.
The assortment of cyp450 isoenzymes

The assortment of cytochrome P450 (CYP450) isoenzymes

Image by Lecturio.

Factors affecting drug metabolism

  • Genetic differences of CYP450
  • Competitive 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, ritonavir, cimetidine, grapefruit juice, cimetidine, fluconazole
    • 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 inhibitors: irreversible enzyme/receptor inhibition, e.g., secobarbital
  • Induction of CYP450:
    • Antiseizure medications, ethanol, St. John’s Wort, rifampin
  • Inhibition of P-glycoprotein (multidrug resistant 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
    • Inhibitors include verapamil and grapefruit juice.
    • Medications metabolized by MDR1 include cyclosporine and digoxin
  • Amount of blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. 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

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 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)
    • Rifampin
    • Carbamazepine
    • Griseofulvin
    • Phenobarbital
    • Smoking
    • St. John’s wort
  • Inhibitors: PACMAN-G
    • Protease inhibitors
    • Azole antifungals
    • Cimetidine 
    • Macrolides
    • Amiodarone
    • Nondihydropyridine (non-DHP) calcium channel blockers Calcium Channel Blockers 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) (CCBs)
    • Grapefruit juice

Pharmacodynamics: Drug Receptors and Effectors

Receptors are macromolecules involved in chemical signaling between and within cells. 

  • These receptors may be located on the cell surface membrane or within the cytoplasm:
    • Cell surface receptors have a transmembrane part that connects them to the cytoplasm:
      • G-protein–coupled receptors
      • Tyrosine kinase receptors
      • Ion channels
    • Intracellular receptors (e.g., steroid receptors): The drug or ligand must be lipophilic. 
      • Steroid receptors
      • Thyroid hormone receptors
      • Vitamin A and D receptors
  • A drug can bind a specific molecular region of the receptor called the recognition site.
    • The recognition site of a drug may be different from that of another drug binding to the same receptor.
  • A drug binding to a receptor can activate or deactivate it, leading to increased or decreased function:
    • Agonists activate receptors to produce the desired response.
    • Antagonists prevent receptor activation: 
      • Can be reversible or irreversible (suicide antagonists)
      • Competitive antagonists prevent binding of the agonist to the receptor.
      • Noncompetitive antagonists allow binding of the agonist to the receptor but reduce or prevent its effect.
  • A drug’s ability to affect a given receptor 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 at any given instant 
      • A drug’s affinity and activity are determined by its chemical structure.
      • A drug’s affinity for the receptor determines the amount of drug needed to produce a therapeutic effect.
    • Intrinsic efficacy: degree to which a ligand activates receptors and leads to cellular response
  • The duration of time that the drug–receptor complex persists determines the pharmacologic effect :
    • Transient occupancy of the receptor produces the desired pharmacologic effect
  • Receptor up- and down-regulation: Receptor density is proportional to receptor binding.
    • Low drug concentration leads to up-regulation of receptors 
    • High drug concentration leads to down-regulation of receptors 
  • Tolerance: reduced drug effect over time due to changes in number and function of receptors
  • 2nd messengers: intracellular molecules activated in response to drug–receptor interaction. Example: 
    • Drug (epinephrine) binds to the receptor G-protein.
    • The receptor makes a change in the G-protein.
    • G-proteins dissociate and bind to the effector (adenylyl cyclase).
    • The effector catalyzes a reaction that increases the concentration of the 2nd messenger (cAMP)
    • cAMP increases heart rate, dilation of skeletal muscle blood vessels, and breakdown of glycogen to glucose.

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. These effects are measured and can be visually represented through curves.

Dose–response curves

  • Graphical representations of the relationship between the dosage 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
  • Emax: 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
  • Dose of the drug on the x-axis, and maximal % of bound receptors on the y-axis
  • Expressed as a sigmoid-shaped log curve
  • Kd (dissociation constant):
    • Defined as the drug concentration that results in 50% of receptors being bound 
    • Lower Kd → higher binding affinity of drug for receptor
    • Higher Kd → weaker binding affinity of the drug for receptor
    • Maximal biologic response (Bmax) does not always require full receptor occupancy by drug
    • Sometimes ED50 is achieved at a drug concentration less than Kd; this is due to the presence of “spare” receptors.
    • Spare 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 shape
  • E50 : drug dose that elicits the defined drug effect in 50% of subjects
Quantal dose–response curve

Quantal dose–response curve (looks at population, not single receptors) noting the dose of a drug that produces a predetermined effect in 50% of subjects (E50)

Image by Lecturio.

Toxicity 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 (kill–response curve)
    • Therapeutic window: 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 (TI): TD50/ED50 
    • The higher the TI, the safer the drug
Graph of a toxicity curve

Graph of a toxicity curve:
The blue dose–response curve represents a drug’s desired effect in a population, and the red dose–toxicity curve represents the drug’s undesirable effect. The therapeutic ratio, or index (TI), lies between the 2 curves and equals dose for a toxic effect in 50% of population/drug concentration that produces 50% maximal effect (TD50/EC50), starting at the 50% maximal effective dose and ending at the 50% toxic dose. The inset shows the relation between therapeutic ratio and adverse effects seen. The greater the therapeutic ratio, the fewer occurrences of adverse effects, and vice versa.

Image by Lecturio.

Potency curves

  • Potency is determined by the affinity of a drug for its receptor: 
    • 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.
Potency curve

Illustration of dose–response curves of different drugs for comparison of their concentration needed to produce a 50% maximal effect (EC50):
Emax is the maximal effect. Lower EC50 = greater potency. The drug farthest to the left on the graph (represented by the dotted gray line) has the highest potency of the 4 drugs plotted because it has the lowest concentration (indicated on x-axis) needed to produce a 50% maximal effect. Shifting from the curves left to right, the potency of the drugs decreases, with the solid gray line to the far right being the least potent drug.

Image by Lecturio.

Elimination and Excretion

Rate of elimination

Elimination is the process of conversion of a drug to inactive metabolites, which are ultimately excreted from the body.

  • Liver (hepatic): primary organ for metabolic elimination of drugs
  • Kidney (renal): primary organ for excretory elimination of drugs

Rate of elimination of drug (mass/time) = clearance x concentration.

Clearance

  • Volume of plasma cleared of drug per unit time (volume/time) 
  • Total systemic clearance (CLtotal):
    • A drug can be cleared through many pathways and organs.
    • CLtotal is the sum of all relevant clearances.
    • CLtotal = CLhepatic + CLrenal + CLpulmonary + CLother

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) 
  • Determined by the drug’s plasma concentration and whether it undergoes active secretion 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 can be calculated:
    • GFR 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 is used to approximate GFR and measure kidney function.
    • Creatinine clearance is the volume of plasma 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, and muscle mass.
  • 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) 
    • Chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease-epidemiology ( CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease-EPI): uses age, race, serum creatinine, sex 
    • Equations can overestimate GFR because creatinine undergoes tubular secretion.
  • When not to use creatinine-based renal clearance equations:
    • Unstable creatinine concentrations
    • Extremes in muscle mass (bodybuilders) or diet (anorexia)
    • In individuals who are paraplegic or otherwise immobile
    • Muscle wasting diseases (e.g., Duchenne muscular dystrophy Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder that is caused by a mutation in the DMD gene. The mutation leads to the production of abnormal dystrophin, resulting in muscle-fiber destruction and replacement with fatty or fibrous tissue. Duchenne Muscular Dystrophy)
    • Vegetarian or low-meat diet
    • Creatine dietary supplements
    • Extremes of age 
  • Cystatin C–based renal clearance equations:
    • More accurate endogenous renal filtration marker than creatinine
    • Cystatin C is a protease inhibitor produced by all nucleated cells.
    • Undergoes filtration, but not secretion or reabsorption 
    • CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease-EPI cystatin C equation is used to measure renal clearance in patients with low muscle mass.
Creatinine filtration

Creatinine is the primary renal filtration marker used clinically to approximate the 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):
Creatinine is freely filtered and is not reabsorbed. However, creatinine is also secreted from the peritubular 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, causing around a 10% overestimation of GFR.

Image by Lecturio.

Biliary excretion

  • Some drugs are extensively excreted in the bile.
  • These drugs undergo active transport against a concentration gradient.
  • Drugs are more likely to be excreted in bile if:
    • They have high molecular weight
    • They contain polar and lipophilic groups
  • Conjugation with glucuronic acid facilitates biliary excretion.
  • The enterohepatic cycle limits biliary excretion of drugs.

Elimination kinetics

  • Half-life (T1/2): time (in minutes or hours) required for the plasma concentration of a drug to decrease by 50% after the completion of drug 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 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 is independent of the concentration of the drug
    • Also known as saturable, nonlinear, or concentration-independent kinetics
Table: Example of a drug that undergoes zero-order elimination kinetics
Hours Amount of drug (mg/L) remaining in the body % of drug eliminated Amount of drug (mg/L) eliminated
0 1
1 0.85 15 0.15
2 0.70 18 0.15
3 0.55 21 0.15
4 0.40 27 0.15
5 0.25 38 0.15
Note that an equal amount of drug, 0.15 mg/L, is eliminated every hour. Though not shown in the table, at 6 hours there would be an amount of 0.10 mg/L (60%) remaining in the body, which is less than 0.15 mg, so after 6 hours, only the remaining amount of ≤ 0.10 mg is eliminated.

References

  1. Benet, L.Z., Zia-Amirhosseini, P. (1995). Basic principles of pharmacokinetics. Toxicol Pathol 23:115–123. https://pubmed.ncbi.nlm.nih.gov/7569664/
  2. Currie GM. (2018). Pharmacology, Part 1: Introduction to pharmacology and pharmacodynamics. J Nucl Med Technol 46:81–86. https://pubmed.ncbi.nlm.nih.gov/29599397/
  3. Dilger JP. (2006). From individual to population: the minimum alveolar concentration curve. Curr Opin Anaesthesiol 19:390–396. https://pubmed.ncbi.nlm.nih.gov/16829720/
  4. Farinde A. (2021). Overview of pharmacodynamics. Merck Manual Professional Edition. Retrieved July 24, 2021, from https://www.merckmanuals.com/professional/clinical-pharmacology/pharmacodynamics/overview-of-pharmacodynamics
  5. Merck Manual Professional Edition. Retrieved July 24, 2021, from https://www.merckmanuals.com/professional/clinical-pharmacology/pharmacokinetics/overview-of-pharmacokinetics
  6. Marunaka Y, N Niisato N, Miyazaki H. (2005).  New concept of spare receptors and effectors. Membr Biol 203:31–39. https://pubmed.ncbi.nlm.nih.gov/15834687/
  7. Shahbaz H, Gupta M. (2020). Creatinine clearance. In: StatPearls. Treasure Island (FL): StatPearls Publishing. Retrieved July 25, 2021, from https://pubmed.ncbi.nlm.nih.gov/31334948/

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