Drug Distribution Flashcards
What are important variables to the rate of delivery of a medication? What tissues receive medication first? What causes medication to diffuse into interstitial fluid easily?
- cardiac output, regional blood flow, capillary permeability, and tissue volume
- well-perfused organs receive most drug (liver, kidney, brain)
- high permeability of capillary endothelial membrane (except in brain)
What major ways that drugs distributed into the body?
- bulk flow: via the blood
- diffusional transfer: via membranes (4 ways, thru pores, diffusion thru lipid membranes, transport across membrane, pinocytosis or phagocytosis)
What contributes to the diffusion gradient of a drug?
concentration of unbound, unionized drug
State the energy requirements, carrier necessity, direction, saturable, and example of the following: passive, facilitated, and active transport
Passive: no energy, no carrier, down gradient, no saturation, ethanol is an example
- facilitated diffusion: no energy, yes carrier, down gradient, yes saturable, amino acids into the brain is an example
- active transport: yes energy, yes to carrier, against gradient, yes saturable, penicillin in kidney, sodium pump
Draw the flow chart of major water compartments with percentages and liter amounts
Pg 31 of week 1 course notes
What plasma protein do acidic and basic drugs bind to for transport? What determines the total drug in plasma that is bound? (3)
- acidic: negatively charged albumin
- basic: 1-acid glycoprotein (acidic)
- drug concentration, affinity of binding sites for the drug, number of binding sites
At low concentrations of drug, the fraction bound is a function of what? At high concentrations of drug, the fraction bound is a function of what? Plasma binding is a ____, and ____ process
- low: concentration of binding sites and the dissociation constant
- high: number of binding sites and drug concentration
- nonlinear, saturable
T/F drugs bound to plasma proteins are active for use
False, only unbound drug is in equilibrium across membrane and is active
What affect does a drug binding to plasma protein have on glomerular filtration, renal tubular secretion, and biotransformation?
- glomerular filtration: limits because this process does not immediately change the concentration of free drug in plasma (water is also filtered)
- renal tubular secretion: does not limit
- biotransformation: does not limit. both because these processes lower the free drug concentration, and this is followed rapidly by dissociation of drug from the drug-protein complex, thereby re-establishing equilibrium between bound and free drug
Give the equation for free fraction of drug and dissociation constant of the drug-protein complex
-what is alpha or free fraction? What is true about the effect of concentration to alpha?
-free fraction= drug/ (drug + drug-protein complex)
- dissociation constant= conc (P)* conc (D)/ (conc PD)
- alpha= free drug conc/ total drug conc and is constant only in a limited range of drug concentrations. Too much drug, and it begins to increase
Discuss what type of drug distrubtion occurs in bone (what can accumulate and an example of how it is used for treatment)
- tetracycline antibiotics and heavy metals can accumulate in bone by adsorption onto the bone crystal surface and join the crystal lattice
- bisphophonates (sodium etidronate) bind tightly to hydroxyapatite crystals in mineralized bone matrix. etidronate is resistant to degradation by pyrophosphatases and thus stabilize bone
What are some properties that determine drug entry into the brain? (4) What reduces the blood-brain barrier?
- molecular weight: compounds w/ MW > 15,000 Dal won’t go through
- lipid solubility: the better, the more in the brain
- fraction of drug unionized at phsyio pH: no charge can enter
- protein binding: only free fraction contributes to concentration gradient
- inflammation due to meningeal and encephalic inflammation leads to increased permeability
What are the important efflux transporters of the brain? Where else do these occur?
- Pgp (MDR 1 protein)
- organic anion transporting polypeptide (OATP)
- OATP polymorphs forms are in the GI, liver, and kidney
What is the issue with drugs entering the brain that are highly lipid soluble?
-they become inactive when they deposit in fat and thus the duration of action for highly lipid soluble brain drugs is more dependent on sequestration into fat as opposed to half life (important concept)
What is the pH in the placenta compared to mother? What factors determine transfer of drugs from mom to baby? What things can cross?
- placenta pH: 7-7.2 (slightly more acidic so attracts basic drugs)
- factors: lipid solubility, plasma binding, degree of ionization
- only very large molecules (heparin and proteins) can’t cross
