G1. Drug adsorption and distribution Flashcards
The physiochemical properties of the molecule determine what?
-determine rate of diffusion
-relative lipid or aqueous solubility
affects speed and extent of absorbtion
major factors of physiochemical properties?
-charge or polarity
-size
will un-ionised or ionised molecules cross the lipid bilayer by passive diffusion?
Only uncharged (un-ionized) molecules will cross lipid bilayers by passive diffusion. Most drugs are weak acids or bases. ONE NOTE
Ionisation state depends on?
-pH of environment (i.e. concentration of H+ ions)
-pKa of drug (pH at which 50% of molecules are in each state)
variation in pH through GI tract?
ONE NOTE
What factors affect the drug crossing the membrane barriers to the reach the blood vessel lumen?
Factors that affect this include:
-Structure of barriers (epidermal/mucosal layer, capillary structure)
-Concentration gradient across membrane (influenced by blood flow)
-Surface area available for transfer
-Residence time at membrane
-First pass metabolism
Describe bioavailability (F)
-A measure of how much drug is absorbed and reaches the systemic circulation
-Normally expressed as a fraction or percentage
-Determined by comparison of a dose delivered by the oral route to the same dose delivered by intravenous injection
what are the two types of bioavailability?
-Absolute bioavailability
-Relative F may be given by comparison to other routes of administration
what is another way of measuring drug absorption, apart from bioavailability?
-Measures from plasma concentration time course
-time to peak to tmax
-maximum concentration is Cmax
ONE NOTE
Describe the variations across the life span for absorbtion?
-Gut maturation is incomplete in newborn
-Intestinal transit time shorter in newborn, longer in elderly
-Gastric pH reduced in both newborn and elderly
(Varies over first few years of life)
-Not all routes equally practical (e.g. swallowing pills)
Describe plasma protein binding to drug
-Plasma proteins, such as serum albumin, act as carriers for poorly soluble metabolites
-Many drugs bind to these carrier proteins, and are also transported around the circulation
-The binding is reversible, so e.g. fatty acids are delivered to cells effectively despite lack of solubility
-Binding interactions with plasma proteins strongly influence drug pharmacokinetics
What are the consequences of plasma proteins binding to drug?
-Binding removes drug from free solution
-Drug no longer free to diffuse into surrounding tissue
-Binding proteins act as a reversible “sink” increasing total amount of drug in blood
-Aids absorption and transport of drug
-Slows elimination
-Binding proteins normally in excess of active drug concentrations, but saturation can cause non-linear dosing effects
-Very high affinity binding (>99%) can restrict the drug to plasma
-Competition for binding sites can lead to drug interactions
Describe the dynamic equilibrium between the bound/ free drug with plasma protein e.g serum albumin
-Drug A and Drug B share a common binding site on the plasma protein.
-Thermodynamic motion leads to chance collision
-Electrostatic binding forces between drug and plasma protein can be overcome by thermal energy
-90% of drug bound is equivalent to one molecule being bound 90% of the time
ONE NOTE
What is free concentration?
Free concentration determines concentration gradient and direction of diffusion
ONE NOTE
What is transcytosis?
brings proteins and and macromolecules across endothelium via vesicles
ONE NOTE
Describe blood brain barrier
-Very effective diffusion barrier
-Tight junctions between endothelial cells, pericytes and glial limitans are multiple barriers to drug escape
-Only lipophilic or transported drugs can access cerebrospinal fluid (and brain parenchyma)
ONE NOTE
Describe placenta
-Drug must pass into maternal blood pool, and then enter foetal circulation (by passive diffusion or active transport)
-Risk of teratogenic or embryotoxic effects
-Lipophilic drugs have ready access
-Drugs with high plasma protein binding affinity do not
ONE NOTE
Describe breast milk
-Alveolar apical cells form a tight-junction limited lipid barrier between capillaries and alveolar lumen
-Diffusion into milk therefore limited by lipophilicity and size
ONE NOTE
Describe tissue depots
-Drug can accumulate in binding sites or intracellular organelles
-May be target site, other proteins, lipid compartments, etc.
-Time course for accumulation depends on perfusion of organ system and drug pharmacokinetics
-Adipose tissue a major reservoir for lipophilic drugs
-Redistribution can occur over time
Describe adipose tissue
-Located in skin (subcutaneous), around internal organs (visceral), breasts, and in bone marrow.
-Composed of adipocytes: cells with large intracellular vacuoles filled with lipids
-Lipid soluble drugs can accumulate in this reservoir
-Increase in adipocyte size (and possibly number) in obesity
Drugs will be distributed throughout the body in what different compartments?
-Extracellular fluid (plasma, interstitial fluid, lymph)
-Intracellular fluid (cell contents)
-Transcellular fluid (CSF, peritoneal, intraocular, synovial etc.)
-Fat
-Bound to protein
what is volume distribution (Vd)?
Theoretical volume of plasma that would accommodate total drug amount at the measured plasma concentration
what is the apparent volume of distribution (Vd) equation?
Vd= total amount of drug in system (Q)/ plasma concentration of drug
-Q will vary with time due to elimination
ONE NOTE
What are the volumes of fluid compartments and what does it indicate?
-Plasma fluid≈ 3 litres
-Extracellular fluid ≈ 12 litres
-Total body water ≈ 40 litres
-Vd > 40 litres indicates some storage of drug in tissues
-Vd < 15 litres suggests drug is largely restricted to plasma and interstitial fluid
Describe variation across life span: distribution
-Body composition changes with age
(Higher fat:lean tissue ratio in infants, Obesity increasing with age)
-Relative volume of fluid compartments varies
-Vd tends to be higher in infants
-Pregnancy adds placental and breastmilk compartments
-Plasma protein synthesis in the liver declines with age
-Renal function affects tissue fluid volumes
-Oedema and diuretic use
