Pharmacokinetics Principles

• Pharmacokinetics describes what the body does to the drugs

Pharmacokinetics Principles

• Involves absorption, distribuiton, metabolism and excretion
• ADME principles apply to the concentration variations of a drug in plasma and its action site
• Movement of drugs involves passage across biological barriers such as cell membranes, drug transport and capillary walls

Cell Membrane Passage

• Passive transport involves diffusion of lipophilic molecules along a concentration gradient without energy consumption
• Active transport requires energy to move molecules against the concentration gradient
• Endocytosis is a process by which cells absorb molecules by engulfing them

Capillary Walls Passage

• Continuous capillaries are found in the nervous system and muscle tissue
• Fenestrated capillaries are found in the kidney glomerulus and intestinal mucosa
• Discontinuous capillaries are found in the liver and bone marrow
• Lipophilic drugs can cross cellular membranes
• Hydrophilic drugs can cross through intercellular spaces

Administration Routes

• Administration can be systemic or topical
• Systemic administration includes enteric routes (oral, sublingual, rectal) and parenteral routes (intramuscular, subcutaneous, inhalation, dermal)
• Topical administration involves cutaneous, intra-articular, digestive, ocular, and intra-rachidian application
• Absorption is the drugs entry into systemic circulation

Factors that Influence Absorption

• Drug characteristics, such as size, pKa, and lip solubility, are important
• Preparations like tablets, capsules, or solutions affect absorption
• Individual physiology includes the available area for absorption, contact time, tissue thickness, blood flow, and pH

Oral Administration

• It involves drug disintegration and dissolution
• Absorption factors includes dose, time of contact at the absorption site, surface area, and blood flow
• It is affected by the pH of the gastrointestinal tract, prescence of food, GI motility, and enzyme activity
• Advantages: convenience, cost-effectiveness, good absorption for many drugs
• Limitations: Lactation time, possible drug inactivation by gastric juices, irritation to the GI tract, hepatic metabolism, and individual cooperation
• First-pass metabolism impacts the bioavailability of drugs taken orally
• The enterohepatic cycle prolongs the drug's effect in the body

Other Systemic Administration Routes:

• Intravenous: Direct injection into the bloodstream, bypassing absorption processes
• Used for drugs poorly absorbed, for rapid effect, large volumes, controlled concentrations, and with irritant drugs
• Intramuscular: Injection into muscle tissue
• Allows administration of aqueous solutions for rapid absorption, or oily preparations/suspensions for slower absorption
• Subcutaneous: Injection under the skin
• Suitable for aqueous solutions with rapid absorption and slower-release preparations
• Inhalation: Delivers drugs via gases or vapors for rapid absorption

Additional Systemic Routes:

• Nasal: Absorption of drugs through the nasal mucosa
• Topical: Effects drugs to the lungs and bronchi
• Transdermal: Application of drugs onto the skin
• Sublingual: Rapid absorption due to rich blood supply
• Rectal: Erratic absorption
• Intrathecal/Intraventricular: Introduction of drugs into the cerebrospinal fluid

Absorption Parameters

• Absorption depends on administration route, absorption speed, absorbed quantity, and plasma concentration
• Bioavailability measures the fraction of the administered dose that reaches systemic circulation
• Bioequivalence occurs when drug formulations show similar bioavailability and time to peak concentration

Drug Distribution in the Body

• Distribution depends on drug's physicochemical characteristics, blood flow, anatomical barriers, transmembrane gradients, and binding to plasma/tissue compounds
• It is also affected by transport mechanisms, the blood-brain barrier, and the placental barrier
• Key influencer: cardiac output and local blood flow
• The distribution of drugs is not uniform

Blood Flow

• Organs with high blood flow (brain, heart, liver, kidneys) receive drugs more rapidly

Blood-brain Barrier

• Only highly lipophilic drugs or those with specific transport systems can cross the blood-brain barrier

Factors that Influence Drug Distribution

• Lipid solubility, ionization, cardiac output, local blood flow, capillary permeability, presence of tissue-specific transporters, and binding to plasma proteins
• Plasma proteins like albumin, alpha1-glycoprotein and lipoproteins, binds to drugs
• Drugs are distributed across vascular, interstitial, and intracellular compartments

Drug Distribution

• It is not uniform, which may lead to drug redistribution

Saliva Distribution

• Drug distribution in saliva occurs through passive diffusion, with salivary drug concentration depending on lipophilicity, molecular size, pH, and saliva flow
• Adverse effects includes alterations in oral surfaces, decreased salivation, gingival hyperplasia, and opportunistic infections
• Therapeutic effects involves consistent drug levels in saliva

Special Delivery Systems

• Nano-particles or micro-spheres can be designed for biodegradable targeted release to combat cancer
• Liposomes is used for hormonal contraception due to targeted hormones release

Apparent Distribution Volume

• It is the ratio of the amount of drug in the body to the drug concentration in plasma
• Total fluid volume in the body is about 42 liters

Biotransformation (Metabolism)

• Involves enzymatic alteration of a drug's chemical structure, creating metabolites that are frequently inactive and water-soluble
• Liver are often very active in drug Metabolism
• Metabolism can occur in the liver, skin, lungs, plasma, kidneys, and intestinal wall
• Microsomal liver enzymes have the capability for biotransformation
• Cytochrome P450 enzymes are important

Metabolism Reactions

• Oxidation, reduction, and hydrolysis for phase I reactions
• Conjugation of the original drug or metabolites with chemical groups for phase II reactions

Drug Metabolism Cases

• Aspirin (AAS) is metabolized through hydrolysis, forming salicylic acid, and further metabolized via different reactions
• Enzyme induction increases the metabolism rate and reducing plasma concentration, diminishing drug effects
• Enzyme inhibition decreases metabolism, increase serum concentration, which leads to potentialy toxic effects

Drug Excretion

• Drugs are commonly excreted through urine, feces, sweat, saliva, breast milk, and exhaled air

Renal Excretion

• It involves glomerular filtration, passive reabsorption, and active transport in the kidney
• Lipid-soluble drugs are reabsorbed, while polar and ionized drugs stay in the urine

Other Excretion Routes

• Biliary excretion eliminates substances via feces using active transport for anions, cations, and neutral substances
• Pulmonary excretion removes volatile gases, and small amounts through secretions

Clearance

• Depuration ("Clearance") is the rate at which the drug is eliminated and the volume of blood cleared of the drug per unit of time
• It involves the sum of renal and hepatic clearance processes
• Water-soluble drugs can be directly excreted, while lipophilic drugs need metabolism

Influences for Action

• How proteins bind influence protein interaction, metabolism, and excretion
• These interactions have a direct influence on plasma concentration and overall drug effects

Examples

• The rate of drug absorption depends on the preparation as seen by different absorption rates of Ibuprofen in capsule compared to suspension
• Ibuprofen and Paracetamol are absorbed at different rates when taken with food vs. fasting

Examples

• Bioavailabilty, volume, desity and clearance affects how drugs are designed with different variations