Distribution week 1 Flashcards
Vd (volume of distrubution)
The extent of distribution of a drug away from the blood
Name 3 important determinants of blood-tissue partitioning of drugs. Which is the most important?
Lipid solubility and transmembrane pH gradients are important determinants of such uptake for drugs that are either weak acids or bases. However, in general, ion trapping associated with transmembrane pH gradients is not large because the pH difference between tissue and blood (~7.0 versus 7.4) is small.
The more important determinant of blood-tissue partitioning is the relative binding of drug to plasma proteins and tissue macromolecules that limits the concentration of free drug.
What are the two main mechanisms via which drugs are distributed into tissues?
Once the drug has been absorbed, it can be distributed to the rest of the body (site[s] of action).
Distribution is accomplished in two main ways.
- Bulk flow via the blood. In this phase, the physiochemical properties are not important. However this phase can result in patterns of distribution. The tissues that are well perfused will receive more of the drug than the less well perfused tissues.
- Diffusional transfer. Where and how quickly the drug distributes depends upon the drug’s ability to cross the cell membranes that separate the various aqueous compartments of the body, e.g. plasma, interstitial fluid, etc. In general there are 4 ways by which most drug molecules cross cell membranes: (same concepts and processes as discussed in Absorption)
A. diffusion through aqueous pores in, or between, membranes (between the cells).
B. diffusion through lipid membranes
C. transport across the membrane (drugs with the appropriate characteristics may be transported by carriers into or out of cells)
D. pinocytosis or phagocytosis. Pinocytosis is the process of engulfing fluid and nutrients by a cell. Phagocytosis is the engulfing of particulates by a cell. Both require cellular energy. Drugs with large MW (>900 kDal) may cross tissue barriers by these processes.
Termination of drug effect after withdrawal of a drug usually is by metabolism and excretion, but also may result from _______ of the drug from its site of action into other tissues or sites.
redistribution
For a standard 70 kg patient, state the major compartments of the body where water is contained. Also state percentages and amounts of water in L in each compartment.
Drugs acting in the CNS will redistribute from their site of activity (the brain). What does duration of action of the first dose of medication depend on with drugs acting in the CNS? How about after several doses?
- Highly lipid soluble drugs will be redistributed into fat before elimination
- Drugs acting in CNS will redistribute away from their site of activity (the brain)
– Duration of action of 1st dose will depend on rate of
redistribution and not the half-life of the drug
– After several doses, if the fat deposits become saturated, then duration of action will depend on half-life of drug
For drugs that act in the CNS, sequestration into fat deposits represents a loss of activity. For example, the drugs diazepam and lorazepam (benzodiazepines) are used for status epilepticus. They have a long half-
life in the blood. But they have only a limited duration of action in status epilepticus because they come out of the CNS and are sequestered into the fat where they are physiologically inert. Therefore the duration of action is not associated with the half-life of the drug, but rather with the rate of sequestration into the fat deposits. (More about this in CNS Block).
What is apparent volume of distribution?
Explain the calculation of apparent volume of distribution.
What is the smallest possible Vd? The largest?
What information can be gathered from a Vd greater than 40 L?
What plasma protein do acidic drugs bind to? Basic drugs?
acidic drugs: albumin
basic drugs: 1-acid glycoprotein
Define α and how it is calculated.
Explain how this value changes with low and high drug concentrations.
At low concentrations of drug, albumin is in excess and does not get saturated. Therefore, increasing doses give increasing levels of the drug, but the percentage (or fraction) of protein binding remains constant. The fraction of the free drug concentration is known as alpha (α) or free fraction (ff).
α = free drug concentration / total drug concentration
The α for drugs can vary from 0 → 1. Since the measurement of drug in the plasma measures the total (bound + unbound) plasma level, changes in plasma binding do not alter the laboratory result. In some cases this may lead to therapeutic toxicity.
At high concentrations of the drug, albumin may get saturated and α will now increase with increasing drug concentrations. Therefore α is a constant only in a limited range of drug concentrations. However for most drugs, their therapeutic concentrations fall in the range of stable α.
What are 4 properties that determine drug entry into the brain?
Blood-Brain Barrier (BBB).
Not all substances present in the bloodstream can gain access to the brain. Endothelial cells appear to be a barrier for some drugs and substances against entry into the brain. Inflammation may increase the permeability of the blood-brain barrier and under these conditions even ionized compounds may penetrate. (More about this in Antimicrobial Pharmacology).
Some of the properties which determine drug entry into the brain are:
a) molecular weight - compounds with MW >60,000 Dal will not penetrate
b) lipid solubility - the greater the lipid solubility the better the penetration
c) fraction of drug un-ionized at physiological pH – the larger the un-ionized fraction, the greater the penetration since the concentration gradient is larger
d) protein binding –only the free fraction contributes to the concentration gradient
What type of transport (transcellular or paracellular) is used by drugs to get into the brain? Why?
What are the ways in which drugs get into the brain?
The distribution of drugs into the CNS from the blood is unique. One reason is that the brain capillary endothelial cells have continuous tight junctions; therefore, drug penetration into the brain depends on transcellular rather than paracellular transport. The lipid solubility of the non-ionized and unbound species of a drug is therefore an important determinant of its uptake by the brain; the more lipophilic a drug, the more likely it is to cross the blood-brain barrier. Drugs may penetrate into the CNS by specific uptake transporters normally involved in the transport of nutrients and endogenous compounds from blood into the brain and CSF.
What is the function of MDR1 (multidrug resistance protein)-Pgp and organic anion transporting polypeptide (OATP)?
Where is OATP found in the body?
Another important factor in the functional blood-brain barrier involves membrane transporters that are efflux carriers present in the brain capillary endothelial cell and capable of removing a large number of chemically diverse drugs from the cell. MDR1 (multidrug resistance protein) - (P-gp)- and the organic anion transporting polypeptide (OATP) are two of the more notable of these.
The effects of these exporters are to dramatically limit access of the drug to the tissue expressing the efflux transporter. Together, P-gp and the OATP family export a large array of structurally diverse drugs. Expression of OATP isoforms and their polymorphic forms in the GI tract, liver, and kidney, as well as the blood-brain barrier, has important implications for drug absorption and elimination, as well as tissue penetration. Expression of these efflux transporters accounts for the relatively restricted pharmacological access to the brain and other tissues such as the testes, where drug concentrations may be below those necessary to achieve a desired effect despite adequate blood flow. Efflux transporters that actively secrete drug from the CSF into the blood also are present in the choroid plexus . In general, the blood-brain barrier’s function is well maintained; however, meningeal and encephalic inflammation increase local permeability.
How do proteins in the P-gp family transport molecules? How do concentration gradients affect transport?
Where are P-gp proteins found in the body?
P-gp belongs to a superfamily of transport proteins. This family consists of membrane localized transport systems that have similar structures in common. Also, the energy they use for drug transport comes from ATP hydrolysis and does not require protein phosphorylation.
substrate (in) + ATP → substrate (out) + ADP + Pi
P-gp acts as a transmembrane pump which removes substrates from membrane and cytoplasm. From the energy gained by the hydrolysis of 1-3 molecules of ATP, the pump can efflux substrates against high concentration gradients. The substrates have no structural similarities but can intercalate into the membrane and enter the cytoplasm by diffusion.
What factors determine transport across the placenta?
T or F: P-gp and other export transporters are present in the placenta.
Lipid solubility, extent of plasma binding, and degree of ionization of weak acids and bases are important general determinants in drug transfer across the placenta. The fetal plasma is slightly more acidic than that of the mother (pH 7.0-7.2 versus 7.4), so that ion trapping of basic drugs occurs.
True: As in the brain, P-gp and other export transporters are present in the placenta and function to limit fetal exposure to potentially toxic agents.
Explain the exclusivity of the placental barrier to drugs. What will and will not cross the placenta?
The view that the placenta is an absolute barrier to drugs is, however, inaccurate, in part because a number of influx transporters are also present. The fetus is to some extent exposed to all drugs taken by the mother. Passage across the placental barrier is regulated by the same requirements as for passage across the blood-brain barrier. However, only very large molecules, such as heparin and proteins, etc. do not cross the
Small molecules,(less than 1,000 MW), which represent the overwhelming majority of therapeutic agents, will cross the placenta, and represent potential risk to the fetus. In this case, with rare exception, the “barrier” is a myth! Drugs which interfere with embryonic or fetal development are called ‘teratogenic’. A Lecture on this topic will be presented in the GU Block.
Complete the attached table.
MDR1, multidrug resistance protein-1; MRP1, multidrug resistance-associated protein 1; NET, norepinephrine transporter; SERT, serotonin reuptake transporter; VMAT, vesicular monoamine transporter.
