After being absorbed into
the blood, part of the drug binds to plasma protein (the protein in cells is
also associated drug), the drug free is not attached to the protein through a
circuit to turn on the model, in which effect (the receptor), on reserve size,
or metabolized and excreted. Between free drug concentration (T) and protein
complexes - medication (P-T) always have a dynamic balance:
T + P P - T
The process of drug
delivery depends on the circulation area. Depending on the vasculature,
thuongchia body into 3 time (H2)
Two types of factors that
affect the distribution of drugs in the body:
On the side of the body:
the nature of the membrane, the membrane capillaries, the number of binding
sites and pHcua environmental medicine.
Towards drugs: molecular
weight ratio of lipid and water soluble, acidic or base, of ionization, the
affinity of the drug to the receptor.
The drugs linked to
plasma proteins
Location attached
Much attached to plasma
albumin (the drug is weak acid) and vaoglycoprotein (the drug is weak base) by
binding reversibly.
Binding
Depending on the affinity
of each drug to plasma proteins (Table 1)
The drugs linked to
plasma proteins depends on three factors:
The number of drug
binding sites on plasma proteins.
Molar concentrations of
the drug-binding proteins.
Constant associated drug
or drug affinity constants.
Meaning of drug binding
to plasma proteins
How easily absorbed, slow
elimination for high blood protein absorption in place, the drug will be pulled
quickly to the circuit.
Plasma protein stroma,
the drug stockpile, after applying the drug, the drug will be released from the
free-form and form new freedom through biological membranes to exert
pharmacological effects.
Free drug concentration
in plasma and interstitial fluid outside always in equilibrium. When the drug
concentration in interstitial fluid reduction in plasma drug will come out,
will release the drug binding protein drugs to keep the balance.
Many drugs can be
attached to the first position of the plasma proteins, causing the dispute,
depending on the affinity of the drug. Drugs were ejected from the protein will
increase the effect, can be toxic. For example, on the tolbutamid used to treat
diabetes, joint pain now, sharepoint phenylbutazone, phenylbutazone will push
tolbutamid a free-form, causing sudden hypoglycemia.
Sometimes both endogenous
drug pushing, causing poisoning endogenous: salicylates push bilirubin, sulfamid
insulin hypoglycemia push out of position associated with protein.
During treatment, the
initial loading dose to saturate the binding site, then the maintenance dose to
steady work.
In the case of
pathological increase - decrease plasma proteins (such as malnutrition, liver
cirrhosis, renal failure, elderly ...), required dose adjustment.
The redistribution
Common to many of the fat
soluble drug, which acts on the central nervous and intravenous drug use. One
typical example of this phenomenon is anesthetized with thiopental, a
fat-soluble drugs. So much brain perfusion, the drug concentration in the brain
achieve maximum very quickly. When stopped injection, plasma concentrations of
thiopental in rapid decline since the drug diffuses into the tissues,
especially adipose tissue. Drug concentrations in the brain decreases with it
ng plasma. So rapid induction, but the effects are not long passion. As for the
additional dose to maintain anesthesia, drugs accumulate in fatty tissues.
Since this drug is released into the blood to the brain when the drug was
stopped, making drug effects setups become prolonged.
The special distribution
Transporting drugs into
the CNS
Mode of transportation:
the drug must pass 3 "fence":
From brain capillaries in
nervous tissue (the blood - brain): soluble drug in the lipid permeable,
water-soluble drugs are difficult to overcome because of glial cells
(astrocytes - astrocytes) is very close together, at the basement membrane, in
addition to the capillary endothelium.
From the choroid plexus
in the cerebrospinal fluid (BBB - meningitis or reduced blood-CSF) as fence on;
strong lipid soluble drug.
From CSF in neural tissue
(CSF barrier - the brain), performed by passive diffusion.
The determinants of the
speed transport drugs into the cerebrospinal fluid and brain are the same
principles permeate biological membranes, such as:
The level of drug linked
to plasma proteins.
The degree of ionization
of the free drug (depending on pH and pKa).
Distribution coefficient
lipid / water free of the drug is not ionized (solubility in lipids).
Drugs from the CSF is
done m ot part by active transport mechanisms in the choroid plexus (an active
transport system for the weak acid and a different system for the weak base).
From the brain, the drug diffusion mechanism passive, dependent mainly on the
lipid solubility of the drug.
The blood - brain depends
on the age and disease status: in infants and young children, less the amount
of myelin structure "fence" is not enough "tight" so easy
diffusion drugs in the brain. Penicillin failed the normal meninges, but blocks
inflammation, penicillin and other drugs can pass.
BBB nature of a lipid
barrier without pipes, so, for the strong of lipid soluble substances, as there
is no fence. Some small areas of the brain such as the human side of the
hypothalamus, periventricular floor 4, pineal and pituitary lobe after no
fence.
As a result of shipping:
The drug can dissolve in
fat absorbed very quickly into the brain, but it does not stay long (see
"redistribution").
Ionized many drugs,
soluble in fat, hard to penetrate into the central nervous: atropine sulfate,
bearing amine 3, less ionized, enter the CNS; atropine methyl bromide also
bring amine 4, strongly ionized, not to be CNS.
You can change the drug
distribution between plasma and brain by changing the pH of the plasma: In the
treatment of phenobarbital poisoning, transmission of NaHCO 3 to raise blood pH
(7.6) beyond the pH of the cerebrospinal fluid (7.3), making the concentration
of ionized plasma concentration of phenobarbital increases nonionic will take
the form of reduced non-ionized drugs from CSF
in blood.
Transporting drugs across
the placenta
method
Fetal capillaries in the
villi are embedded in the mother's blood pool, so blood between mother and
fetus "placenta". The permeability of capillaries m antenna increases
with gestational age fetus. The absorption and also according to the general
rule:
The fat-soluble drugs
passive diffusion: anesthetic vapor, (protoxyd nitrogen, halothane,
cyclopropan), thiopental.
Active transport: amino
acids, ions Ca ++, Mg ++.
Competent cells
(pinocytosis) with drops of maternal plasma.
result
Except for the
water-soluble drugs have molecular weights larger than 1000 (such as dextran)
and the primary amine 4 (galanin, Neostigmine) did not pass the placenta, many
drugs can enter the fetal blood, dangerous for pregnant (phenobarbital,
sulphonamides, morphine), therefore, should not be taken as
"placenta".
The amount of protein-
bound drugs in maternal blood plasma drug concentration is high, low free, drug
free only new blood to be human, in this part of the drug to attach to human
blood plasma proteins, so the concentration free drug in the blood lower. To
obtain free drug concentrations similar to maternal blood, need some time to 40
minutes. For example, injection of thiopental to the mother during labor, and
after 10 minutes, the mother is blood concentrations of thiopental in children
has not achieved the maze, which explains why the mother was sleeping but can
lay out child I was still awake.
In addition, the placenta
has many as cholinesterase enzyme, monoamine oxidase, hydroxylase may
metabolize the drug, to reduce the effect to protect the fetus.
The cumulative drug
Some drugs or poisons
have very tight linkage (usually covalent link) with a number of tissues in the
body and is retained for a long time, tens monthly nă m after dosing, with the
only is 1: DDT linked to fatty tissue, tetracycline attached to bone, tooth germ,
As keratinocytes attached to ...
Some drug accumulation in
skeletal muscle cells and other tissues with higher concentrations in the
blood. If the binding is reversible drug, the drug will be liberated from the
"reserves" in the blood (see "redistribution"). Quinacrin
concentrations in liver cells when used long-term drug may be higher plasma
concentrations several hundred times due to liver cells with active transport
processes quinacrin pulled into cells.
Pharmacokinetic
parameters of the distribution: the volume of distribution (Vd)
define
The volume of
distribution indicates an apparent volume (no really) contains all the medicine
has been taken into the body to the concentration of the drug concentration in
the same command ết.
Vd = (D / Cp) lit
D: dose of medication
into the body (mg) intravenously. If another way to take into account the
bioavailability: D x F
Cp: plasma concentrations
measured immediately after delivery and before elimination. Eg, there is no
real volume, measured by L (liter) or L / kg.
For example, a person
weighing 60 kg, there may be water in 36 L (60% of body weight), was taking 0.5
mg (500 g) with F oral digoxin is 0.7. Measurement of plasma digoxin
concentrations found Cp = 0.7 ng / mL (0.0007 mg / mL).
So: Vd = (0.5 x 0.7) /
0.0007 = 500L or 8.3 L / kg
Vd = 500L, grew by nearly
14 times the amount of water in the body so that the apparent volume.
Reviews and clinical
significance
Vd is the smallest in
plasma volume (3L or 0,04L / kg). There is no limit on the Vd. Ie the greater
the drug proved much more attached to the model: the treatment of bone and
joint infections should choose appropriate antibiotics have large Vd.
Knowing eg drug,
calculate the dose needed to achieve hats g desired plasma:
D = Vd x Cp
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