An Introduction to Pharmacokinetics and ADME Flashcards
Define the terms pharmacokinetics and pharmacodynamics
- Pharmacokinetics: “What the body does to the drug”
Pharmacokinetics refers to the study of the absorption, distribution, metabolism, and excretion (ADME) of drugs. It describes the movement of a drug through the body over time and how the body processes the drug.
Absorption: How the drug enters the bloodstream (e.g., through the gastrointestinal tract, skin, or lungs).
Distribution: How the drug is transported throughout the body and distributed to various tissues and organs.
Metabolism: How the drug is chemically altered by the body, typically by enzymes in the liver, which may deactivate the drug or convert it into an active form.
Excretion: How the drug is removed from the body, usually through the kidneys (urine), liver (bile), or other excretory pathways.
Pharmacokinetics helps determine drug dosages, frequency of administration, and the duration of drug effects.
- Pharmacodynamics: “What the drug does to the body”
Pharmacodynamics refers to the study of the effects of drugs on the body and the mechanisms of action through which these effects occur. It focuses on how a drug interacts with its target sites (e.g., receptors, enzymes) and produces its therapeutic effect or side effects.
Receptor Binding: Many drugs exert their effects by binding to specific receptors on cells, which triggers a biological response.
Dose-Response Relationship: The relationship between the dose of a drug and the magnitude of its effect.
Therapeutic Effect: The desired effect of the drug, such as pain relief, lowering blood pressure, or curing an infection.
Toxicity: The harmful effects that occur when the drug concentration exceeds a certain level.
Pharmacodynamics helps explain the mechanism of action of a drug and its efficacy, potency, and side effects.
Define ‘safe and effective’ in relation to medication
A safe medication causes minimal harm and has an acceptable risk-benefit profile, meaning its benefits outweigh potential risks like side effects or toxicity. It should have manageable side effects, a wide therapeutic window, and should not interact harmfully with other drugs.
An effective medication achieves the desired therapeutic outcome, whether by curing a condition, managing symptoms, or improving quality of life. Effectiveness is measured through clinical trials and real-world results, ensuring the drug works as intended in both ideal and routine conditions.
In short, a safe and effective medication provides the intended benefits with minimal risk when used as directed.
Recognise the scale of the problem in terms of medication-related harm
Medication-related harm is a significant global issue, contributing to hospital admissions, morbidity, and mortality. Key points include:
Prevalence: 5-10% of hospital admissions are due to adverse drug reactions (ADRs), and medication errors are common, often leading to serious harm or death.
Economic Impact: Medication-related harm costs healthcare systems billions annually, including direct costs from hospitalizations and treatments.
Global Burden: Over 230,000 deaths annually are attributed to medication errors and ADRs, with overuse of medications contributing to global issues like antimicrobial resistance.
Risk Factors: Elderly patients, polypharmacy, chronic conditions, and poor communication are major risk factors.
Prevention: Strategies to reduce harm include improved prescribing, patient education, medication reviews, and pharmacovigilance.
Describe what is meant by therapeutic index
The therapeutic index is a measure used to evaluate the safety of a drug. It is defined as the ratio between the toxic dose and the effective dose of a drug. The therapeutic index provides an indication of how much of a drug can be administered safely before it reaches toxic levels.
A higher therapeutic index suggests a larger margin of safety, meaning there is a greater difference between the dose needed for therapeutic effects and the dose that could cause harm. Conversely, a lower therapeutic index indicates a smaller margin of safety, requiring more careful monitoring and dosing.
Formula:
The therapeutic index is typically calculated as:
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Where:
LD₅₀ = Lethal dose for 50% of the population (dose that causes death in 50% of individuals)
ED₅₀ = Effective dose for 50% of the population (dose that produces the desired effect in 50% of individuals)
Key Points:
High Therapeutic Index: Drugs with a large difference between the effective dose and toxic dose are considered safer, as there is a greater range between the dose that provides therapeutic benefits and the dose that could be harmful.
Example: Penicillin has a high therapeutic index, as the therapeutic dose is far lower than the toxic dose.
Low Therapeutic Index: Drugs with a small difference between the effective dose and toxic dose are considered more dangerous. These drugs require more precise dosing and careful monitoring.
Example: Warfarin (an anticoagulant) has a low therapeutic index. Small changes in dose or diet can lead to serious bleeding complications, so regular monitoring of blood levels is necessary.
Clinical Relevance:
Drugs with a low therapeutic index (e.g., chemotherapy drugs, warfarin, lithium) require close monitoring to avoid toxicity.
Drugs with a high therapeutic index (e.g., antibiotics like penicillin) are generally safer and have a broader margin for error in dosing.
In summary, the therapeutic index helps determine how safe a drug is by comparing the range between the effective dose and the toxic dose, guiding clinicians on how to administer the drug safely.
Define (in very general terms) absorption, distribution, metabolism and excretion
ADME describes the four key processes that determine how a drug moves through the body:
Absorption: The drug enters the bloodstream after administration.
Distribution: The drug is carried through the bloodstream to various tissues and organs.
Metabolism: The drug is chemically altered, mainly in the liver, to prepare it for elimination.
Excretion: The drug or its metabolites are eliminated from the body, typically via the kidneys (urine), liver (bile), or lungs.
Recognise that the mechanisms that underlie ADME are normal physiological mechanisms
The processes of Absorption, Distribution, Metabolism, and Excretion (ADME) are based on the body’s normal physiological functions:
Absorption: Substances are absorbed into the bloodstream through natural barriers like the GI tract, similar to how nutrients are absorbed from food.
Distribution: Once in the bloodstream, substances (including drugs) are carried to tissues and organs, much like oxygen and nutrients are distributed throughout the body.
Metabolism: The body, mainly the liver, breaks down substances, similar to how it processes nutrients and detoxifies waste products.
Excretion: Waste products, including drug metabolites, are eliminated through the kidneys, liver, and lungs, just as the body removes metabolic waste like urea and carbon dioxide.
In short, the mechanisms that underlie ADME are part of the body’s natural systems for processing and eliminating substances.
List the main routes of administration of medication
Oral (PO): Taken by mouth (e.g., tablets, liquids); convenient but slower absorption.
Intravenous (IV): Injected directly into the vein; rapid effect with 100% bioavailability.
Intramuscular (IM): Injected into a muscle; faster than oral, but slower than IV.
Subcutaneous (SC): Injected under the skin; moderate absorption rate, often self-administered.
Inhalation: Inhaled into the lungs (e.g., asthma inhalers); fast action, targets the lungs.
Topical: Applied to the skin (e.g., creams, patches); localized effect, minimal systemic absorption.
Sublingual (SL): Placed under the tongue; rapid absorption, bypasses digestion.
Rectal: Inserted into the rectum; useful when oral administration is not possible.
Transdermal: Absorbed through the skin via a patch; provides continuous drug delivery.
Ophthalmic: Applied to the eye (e.g., drops, ointments); for eye conditions.
Nasal: Administered through the nose (e.g., sprays, drops); rapid absorption.
Vaginal: Administered in the vagina; used for local treatment of pelvic conditions.
Describe the main principles that govern the movement of drug molecules
- Passive Diffusion
Principle: Drugs move across cell membranes from areas of higher concentration to areas of lower concentration without the use of energy.
Description: This is the most common mechanism for drug absorption and distribution, where drug molecules move across lipid bilayers (cell membranes) according to the concentration gradient.
Factors Influencing Diffusion:
Lipophilicity: Lipid-soluble drugs can more easily pass through cell membranes.
Size of the Drug Molecule: Smaller molecules diffuse more easily.
Concentration Gradient: A higher concentration of the drug on one side of the membrane facilitates faster diffusion. - Active Transport
Principle: This process involves the movement of drug molecules against a concentration gradient, requiring energy (usually in the form of ATP) and specific transporter proteins.
Description: Active transport is used for the uptake of drugs into cells or across biological barriers (e.g., blood-brain barrier). This mechanism allows for the concentration of drugs in certain tissues or organs.
Example: P-glycoprotein is a key transporter protein that pumps drugs out of cells in the liver, kidney, and intestine. - Facilitated Diffusion
Principle: Similar to passive diffusion, but involves carrier proteins to assist drug molecules in crossing cell membranes.
Description: Facilitated diffusion doesn’t require energy but relies on specific proteins to facilitate the transport of molecules that cannot easily diffuse across the lipid bilayer.
Example: Glucose transport into cells via facilitated diffusion. - Filtration
Principle: Movement of drug molecules across membranes due to pressure gradients, particularly in capillaries and kidneys.
Description: In filtration, drug molecules move through pores in the capillary walls or renal glomerulus based on size and pressure differences. This mechanism plays a role in the excretion of drugs in the kidneys.
Factors Influencing Filtration:
Molecular Size: Larger molecules are less likely to be filtered.
Hydrostatic Pressure: Higher pressure can push molecules through pores. - Ionization and pH
Principle: The ionization state of a drug molecule significantly influences its ability to cross cell membranes. Non-ionized (neutral) drugs are more likely to diffuse through lipid membranes.
Description: Many drugs are weak acids or bases, and their ionization depends on the pH of the surrounding environment. Ionized drugs are less lipid-soluble and therefore less able to pass through membranes.
Example: Acidic drugs tend to be non-ionized in acidic environments (like the stomach), enhancing absorption, whereas basic drugs are more likely to be non-ionized in alkaline environments (like the intestines). - Blood Flow and Perfusion
Principle: Blood flow to tissues influences the rate at which drugs are distributed throughout the body.
Description: Organs with high blood flow (such as the heart, liver, and kidneys) receive drugs more quickly. Tissues with lower perfusion (like fat or muscle) may take longer to be reached by drugs.
Example: A drug injected into a muscle will be absorbed and distributed more slowly than one injected into the bloodstream. - Protein Binding
Principle: Drugs may bind to plasma proteins (like albumin) in the blood, affecting their distribution and availability.
Description: Only the free (unbound) form of a drug can cross cell membranes to exert a therapeutic effect. The bound form is typically inactive and can be stored in the bloodstream.
Example: Warfarin, an anticoagulant, binds extensively to plasma proteins, and only the free drug is pharmacologically active. - Lipid Solubility and Partition Coefficient
Principle: The lipid solubility of a drug influences how easily it crosses cell membranes and enters the bloodstream.
Description: The partition coefficient (ratio of drug concentration in lipid vs. aqueous phases) determines a drug’s ability to pass through biological membranes, such as the blood-brain barrier.
Example: Lipophilic drugs (e.g., diazepam) cross the blood-brain barrier more easily than hydrophilic drugs. - Transporter Proteins
Principle: Specialized proteins in cell membranes regulate the movement of drug molecules across barriers.
Description: In addition to active transport, transporters can pump drugs into or out of cells, influencing their absorption, distribution, and elimination.
Example: Organic anion transporters (OATs) in the kidneys help eliminate drugs through urine.
Describe the importance of the kidney and liver in drug elimination and toxicity
- Liver: Metabolism and Detoxification
The liver is the central organ for drug metabolism. It processes drugs, transforming them into more water-soluble compounds that can be more easily excreted through the kidneys or bile.
Roles in Drug Elimination:
Metabolism: The liver converts drugs into metabolites, which can be either inactive (to be excreted) or active (to continue exerting therapeutic effects). Some drugs are converted into inactive metabolites, which are then excreted by the kidneys or through bile. Others are converted into active metabolites, which contribute to the drug’s overall effect.
Phase 1 Metabolism: Enzymes like cytochrome P450 (CYP450) oxidize, reduce, or hydrolyze the drug, making it more hydrophilic and less pharmacologically active.
Phase 2 Metabolism: Involves conjugation reactions (e.g., glucuronidation, sulfation), further making drugs more water-soluble for excretion.
Bile Excretion: The liver secretes some drug metabolites into bile, which is then excreted through the gastrointestinal tract. This process is especially important for lipophilic drugs that are not easily excreted by the kidneys.
Role in Drug Toxicity:
Toxicity from Drug Metabolism: Some drugs are metabolized into toxic metabolites. For example, acetaminophen (paracetamol) is generally safe in therapeutic doses, but excessive use leads to hepatic toxicity through the formation of a highly reactive metabolite that damages liver cells.
Liver Disease Impact: If the liver is damaged (e.g., due to cirrhosis, hepatitis, or fatty liver disease), its ability to metabolize drugs can be impaired, leading to drug accumulation in the body, which increases the risk of toxicity.
2. Kidney: Filtration and Excretion
The kidneys are responsible for eliminating water-soluble drugs and their metabolites from the body. They perform this function through a process involving filtration, reabsorption, and secretion.
Roles in Drug Elimination:
Glomerular Filtration: Drugs and their metabolites are filtered from the blood into the glomerular filtrate (urine precursor) in the kidney’s glomerulus. The rate at which drugs are filtered depends on their size and protein binding (only unbound drugs are filtered).
Tubular Secretion: Certain drugs are actively secreted into the tubules from the bloodstream by transport proteins. This is important for eliminating drugs that are poorly filtered through the glomerulus.
Tubular Reabsorption: After filtration, substances in the renal tubules may be reabsorbed back into the bloodstream, particularly lipid-soluble drugs. Drugs that are water-soluble tend to remain in the filtrate and are excreted in urine.
Role in Drug Toxicity:
Renal Failure and Drug Toxicity: In patients with renal dysfunction (e.g., chronic kidney disease), the kidneys’ ability to excrete drugs is compromised, which can lead to drug accumulation and increased toxicity. Many drugs (e.g., digoxin, lithium, antibiotics) require dose adjustments or careful monitoring in patients with kidney problems.
Nephrotoxic Drugs: Some drugs are directly toxic to the kidneys, causing conditions like acute kidney injury (AKI) or chronic kidney disease. Nonsteroidal anti-inflammatory drugs (NSAIDs), aminoglycoside antibiotics, and contrast agents are examples of drugs that can damage kidney cells.
Key Mechanisms of Toxicity Involving the Liver and Kidney:
Liver Toxicity:
Drug-Induced Liver Injury (DILI): Drugs like acetaminophen, alcohol, and certain antibiotics can overwhelm liver detoxification pathways, leading to liver cell death, hepatitis, or cirrhosis.
Metabolic Toxicity: Some drugs, after undergoing phase I or II metabolism in the liver, form reactive intermediates that bind to cellular proteins and cause damage. For example, acetaminophen overdose can cause liver necrosis through the formation of a toxic metabolite (NAPQI).
Kidney Toxicity:
Nephrotoxicity: Drugs such as aminoglycosides (e.g., gentamicin) and cisplatin can cause acute tubular necrosis or chronic kidney damage by directly injuring renal cells.
Impaired Renal Function: In patients with kidney disease, the reduced ability to excrete drugs leads to the accumulation of drug levels, potentially causing adverse effects and toxicity. Digoxin toxicity, for instance, is a common concern in renal failure due to the reduced renal clearance of the drug.
