3.1 Drug absorption, distribution, and elimination
3 min read•august 9, 2024
Drugs go on a wild ride through your body after you take them. They get absorbed, spread around, and eventually kicked out. This journey affects how well they work and how long they stick around.
Your body's a tough bouncer, though. It's got tricks to keep drugs out of certain places, break them down, and show them the exit. Understanding this process helps explain why some drugs hit hard and fast, while others take their sweet time.
Pharmacokinetic Processes
Absorption and Distribution
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- Absorption involves drug movement from administration site into bloodstream
- Occurs through various routes (, , transdermal, )
- Influenced by factors such as drug formulation, pH, and membrane permeability
- Distribution describes drug spread throughout body tissues and fluids
- Affected by blood flow, lipid solubility, and
- Volume of distribution (Vd) quantifies drug spread extent in body
- Lipophilic drugs cross cell membranes more easily than hydrophilic drugs
- Protein binding impacts drug distribution and effectiveness
- Only unbound drug fraction can exert pharmacological effects
- Albumin and alpha-1-acid glycoprotein serve as major binding proteins
Metabolism and Excretion
- Metabolism involves chemical alteration of drugs in the body
- Primarily occurs in liver through Phase I and Phase II reactions
- Phase I reactions include oxidation, reduction, and hydrolysis
- Phase II reactions involve conjugation (glucuronidation, sulfation)
- Cytochrome P450 enzymes play crucial role in drug metabolism
- CYP3A4, CYP2D6, and CYP2C9 metabolize majority of drugs
- Excretion eliminates drugs and metabolites from the body
- Kidneys serve as primary excretory organ for most drugs
- Other routes include , sweat, and exhalation
- involves glomerular filtration, active tubular secretion, and passive reabsorption
- Enterohepatic circulation can prolong drug presence in body
Drug Bioavailability Factors
Bioavailability and First-Pass Effect
- Bioavailability measures fraction of administered drug reaching systemic circulation
- Expressed as percentage, ranging from 0% to 100%
- Intravenous administration has 100% bioavailability by definition
- Factors affecting bioavailability include drug solubility, permeability, and formulation
- First-pass effect reduces oral drug bioavailability
- Occurs when drug undergoes metabolism in gut wall or liver before reaching systemic circulation
- Can significantly reduce amount of active drug available (propranolol, morphine)
- Sublingual and transdermal routes can bypass first-pass effect
Lipid Solubility and Protein Binding
- Lipid solubility determines drug ability to cross cell membranes
- Lipophilic drugs (benzodiazepines, steroids) easily penetrate tissues
- Hydrophilic drugs (aminoglycosides, heparin) have limited tissue distribution
- Partition coefficient (logP) measures drug lipophilicity
- Higher logP values indicate greater lipid solubility
- Protein binding affects drug distribution and elimination
- Only unbound drug fraction can cross membranes and exert effects
- Highly protein-bound drugs (warfarin, phenytoin) have longer half-lives
- Displacement of protein-bound drugs can lead to increased free drug concentration
- Can result in enhanced drug effects or toxicity
Drug Elimination Concepts
Half-Life and Clearance
- (t1/2) represents time required for drug concentration to decrease by 50%
- Determines dosing frequency and time to reach steady-state
- Calculated using formula:
- Clearance (CL) measures volume of blood cleared of drug per unit time
- Expressed in units of volume/time (L/hr or mL/min)
- Total body clearance equals sum of all elimination pathways
- Elimination rate constant (k) relates to half-life:
- Steady-state achieved after approximately 4-5 half-lives of continuous dosing
Blood-Brain Barrier and Elimination Pathways
- (BBB) protects central nervous system from potentially harmful substances
- Formed by tight junctions between brain capillary endothelial cells
- Limits penetration of many drugs into brain tissue
- Lipophilic drugs (morphine, diazepam) cross BBB more easily than hydrophilic drugs
- P-glycoprotein transporters in BBB actively pump out certain drugs
- Multiple elimination pathways contribute to drug clearance
- Renal elimination predominates for many drugs
- Hepatic metabolism important for lipophilic drugs
- Other routes include biliary excretion and pulmonary elimination
- Clearance can be organ-dependent or organ-independent
- Organ-dependent clearance affected by blood flow and extraction ratio
- Organ-independent clearance follows first-order kinetics
Key Terms to Review (19)
Active transport: Active transport is the process by which substances move across cell membranes against their concentration gradient, requiring energy, usually in the form of ATP. This mechanism is crucial for maintaining cellular homeostasis and enabling the selective uptake of essential molecules and ions, which impacts how drugs are absorbed, distributed, and eliminated in the body.
Alexander Bain: Alexander Bain was a Scottish philosopher and psychologist known for his contributions to the fields of psychology and the philosophy of mind in the 19th century. His work laid important groundwork for understanding the interactions between mental processes and physiological responses, particularly in relation to drug absorption, distribution, and elimination within the body.
Biliary excretion: Biliary excretion is the process by which waste products, drugs, and other substances are eliminated from the body through bile produced by the liver. This mechanism plays a critical role in the elimination of certain drugs and their metabolites, linking it closely to the overall processes of drug absorption, distribution, and elimination. Bile salts, which are key components of bile, help in emulsifying fats for digestion but also facilitate the excretion of non-water-soluble substances from the bloodstream into the intestines.
Blood-brain barrier: The blood-brain barrier (BBB) is a selective permeability barrier that separates the circulating blood from the brain and central nervous system, protecting it from potentially harmful substances while allowing essential nutrients to pass through. This barrier plays a crucial role in maintaining homeostasis and ensuring that the brain functions optimally by controlling what substances can enter from the bloodstream, impacting drug delivery, pharmacology, and neurotechnology.
First-pass metabolism: First-pass metabolism refers to the process by which a drug's concentration is significantly reduced before it reaches systemic circulation. This phenomenon occurs primarily in the liver, where enzymes metabolize the drug after it is absorbed from the gastrointestinal tract but before it enters the bloodstream. Understanding first-pass metabolism is crucial because it affects the bioavailability of drugs, particularly those taken orally, and can influence the pharmacological effects of substances like cannabinoids.
Half-life: Half-life is the time required for the concentration of a drug in the bloodstream to reduce to half its initial value. This concept is crucial for understanding how long a drug remains active in the body, influencing dosing schedules and the overall efficacy of medications. Half-life also impacts drug interactions, effectiveness of therapies, and the duration of action for both natural and synthetic compounds.
Inhalation: Inhalation is the process of breathing in substances, often in the form of gases or aerosols, directly into the lungs. This method of administration allows for rapid absorption of drugs into the bloodstream, providing quick onset of effects and significant bioavailability. It plays a crucial role in how different drugs interact with the body and affects their distribution and elimination.
Intravenous: Intravenous refers to the administration of substances directly into a vein, allowing for rapid delivery and absorption of medications or fluids into the bloodstream. This method is particularly relevant for delivering drugs that require immediate action, such as opioids, and plays a critical role in understanding how drugs are absorbed, distributed, and eliminated in the body. Intravenous administration is also essential for classifying drugs based on their effects and how they interact with the brain's neural pathways.
Onset: Onset refers to the time it takes for a drug to produce its first noticeable effects after administration. This period is critical as it determines how quickly a person may feel the impact of the drug, influencing both therapeutic outcomes and potential side effects. Understanding onset helps in evaluating the effectiveness of a drug and in managing patient expectations regarding when relief or effects will occur.
Oral: Oral refers to the method of administering drugs through the mouth, allowing substances to be absorbed in the gastrointestinal tract. This route is one of the most common ways to take medications, as it is non-invasive and convenient. Understanding oral administration is crucial when looking at how natural and synthetic opioids are used clinically, how drugs are absorbed into the bloodstream, distributed throughout the body, and how their effects can vary based on the drug classification.
Passive diffusion: Passive diffusion is the process by which molecules move across a cell membrane from an area of higher concentration to an area of lower concentration without the use of energy. This movement occurs until there is an equal distribution of molecules on both sides of the membrane and is a fundamental mechanism for drug absorption, distribution, and elimination in the body.
Paul Ehrlich: Paul Ehrlich was a pioneering German physician and scientist known for his work in immunology and pharmacology, particularly the development of the first effective treatment for syphilis using arsenic compounds. His innovations laid the groundwork for modern chemotherapy and established fundamental principles regarding drug absorption, distribution, and elimination.
Peak Effect: Peak effect refers to the maximum intensity of a drug's effect after administration, occurring after it has reached its highest concentration in the bloodstream. This concept is crucial for understanding how drugs interact with the body, as it indicates when the therapeutic or adverse effects are most pronounced. The timing of peak effect can vary widely depending on factors such as the route of administration, the drug's pharmacokinetics, and individual patient characteristics.
Pharmacogenetics: Pharmacogenetics is the study of how an individual's genetic makeup influences their response to drugs. This field aims to understand the variations in drug metabolism, efficacy, and toxicity among different people, ultimately leading to more personalized and effective medication strategies. By examining genetic factors, pharmacogenetics seeks to optimize drug therapy and minimize adverse effects, thereby improving patient outcomes.
Plasma concentration: Plasma concentration refers to the amount of a drug that is present in the blood plasma at any given time. This measurement is crucial for understanding how drugs behave in the body, as it affects their therapeutic effects and potential toxicity. The plasma concentration of a drug is influenced by factors such as absorption rates, distribution throughout tissues, and elimination processes.
Protein binding: Protein binding refers to the process by which drugs attach to proteins in the blood, primarily albumin and alpha-1 acid glycoprotein. This binding affects the distribution of drugs within the body, their efficacy, and their elimination rates, as only the unbound (free) drug can exert therapeutic effects or undergo metabolism and excretion.
Renal excretion: Renal excretion is the process by which waste products and excess substances are removed from the bloodstream through the kidneys, resulting in urine formation. This vital function helps maintain the body's fluid and electrolyte balance, while also facilitating the elimination of drugs and their metabolites from the body, significantly impacting drug elimination processes.
Therapeutic Index: The therapeutic index is a measure of a drug's safety, defined as the ratio between the dose that produces toxicity and the dose that produces the desired therapeutic effect. A higher therapeutic index indicates a wider margin of safety, while a lower index suggests a greater risk for adverse effects, making it crucial for assessing drug dosing and effectiveness.
Tolerance: Tolerance is a physiological process where the body's response to a drug decreases over time, requiring higher doses to achieve the same effect. This can significantly impact an individual's experience with substances and is closely linked to concepts like dose-response relationships, dependence, and addiction.