lecture 7.3 Flashcards
Name an example of a drug that may be displaced by another drug in the plasma and subsequently increase its free drug conc and become fatal
displacement of dicumarol (an oralanticoagulant ) by phenylbutazone
*only 3% of dicumarol is free, additional displacement of 3% increases effects by 100%
What is dicumarol?
naturally occurring anticoagulant that depletes vitamin K
What is phenylbutazone?
non-steroidal antiinflammatory drug (NSAID) for the short-term treatment of pain and fever
What is full form of NSAID?
non-steroidal antiinflammatory drug
What is the characteristic of class 1 drugs in plasma?
high binding affinity to plasma protein
What is the characteristic of class 2 drugs in plasma?
lower affinity for plasma proteins and exist in a higher proportion as free, unbound drug in the bloodstream
How are class 1 and 2 administered simultaneously?
Class 1: dose less than available binding sites
class 2: dose greater than available binding sites
–> Displacement of Class I drug occurs when a Class II drug is administered simultaneously
At what sites can tissue localization occur? What drugs id accumulated at these sites?
- bone: accumulation of lithium or tetracycline through active transport
- thyroid gland: throglobulin responsible for
accumulation - liver: accumulation of antimalarial agent chloroquine
Does local blood flow play a role in the accumulation of tetracycline in bone? Why?
No, blood perfusion of the bone is not extensive.
Active transport and the presence of specific
binding proteins are responsible
Why does antimalarial agent chloroquine accumulate in the liver?
due to its interaction with hepatic DNA
–> intercalates adjacent pairs of the double helix
What is the extent of dsitribution of a drug known as?
volume of distribution (Vd)
What is the formula of Vd?
Amount of drug in body/
Concentration of drug in plasma
(units=liters)
For a 70kg individual, what is the total body water volume?
45L total body volume
–> 15L extracelluar
–10L interstitial
– 5L plasma volume
–> 30L intracellular
For the one-compartment model of distribution of drugs, what is the assumption?
that an administered drug is homogeneously distributed throughout the tissue fluids of the body
How does the two-compartment model of distribution differ from that of one compartment?
contains two or multiple central or
peripheral compartments
What does the central compartment include?
the blood and extracellular fluid volumes of the highly perfused organs (i.e., the brain, heart, liver, and kidney)
What does the peripheral compartment consist of?
relatively less perfused tissues such
as muscle, skin, and fat depots
What does the rate of distribution of a drug from the blood to a tissue depend on?
- extent of drug binding to plasma proteins
- ability of drug to diffuse through tissue membrane –> lipophilic able to diffuse
- degree of perfusion of tissue (blood/min/vol of tissue)
- properties of tissue membrane
What is distributive equilibrium?
the state where a drug has reached a balance between its movement into and out of tissues.
–> rate of drug transfer between blood (plasma) and tissues becomes equal.
The rate of distribution of a drug from the blood to a tissue also depends on ability of that drug to diffuse through tissue membrane. In general, lipophilic drugs are able to diffuse.
True or false
true
Rank the following in decreasing order of perfusion rate:
heart, brain, fat, lungs, muscle, lung
lung, kidney, heart, brain, muscle, and fat
Compare the diffusion of thiopental in muscle and brain.
Thiopental: lipophilic
–> can diffuse into brain and muscle
–> brain perfusion higher, thus diffuses more rapidly in brain
Compare the diffusion of penicillin in muscle and brain.
penicillin: polar
–> cannot diffuse into brain
–> muscle capillaries are porous, can diffuse into muscle
What would be the value of ‘apparent volume of distribution’ if the drug shows extensive tissue binding?
many times the total body size
Name a drug that shows extensive tissue binding and has ‘apparent volume of distribution’ many times that of total body size.
quinacrine
apparent volume of distribution = 500 liters/kg
Name a drug that shows extensive plasma binding and has ‘apparent volume of distribution’ less than total body size.
Digoxin (binds to plasma protein to the extent of 23%)
apparent volume of distribution = 8 liters/kg
How does the volume of distribution of drugs that do not bind to plasma or tissue proteins vary?
between the extracellullar fluid volume (~15 liters) and the total body water (~45 liters).
Name some drugs/ elements/ compounds that are confined to the extracellular water
Insulin, sodium, bromine, and iodine
Name some drugs/ elements/ compounds that are distributed in the total body water
antipyrine, caffeine, and ethanol
What are brain capillaries covered with?
sheath composed of astrocyte foot processes
How do charged drugs enter the brain?
Charged drugs cannot diffuse across the brain endothelial cell unless by carrier-mediated transport
Can charged drugs diffuse across the brain endothelial cells?
No
How do lipid-soluble drugs enter the brains?
diffuse across the various layers of cell membranes
What is the ‘blood-brain barrier’ and why does it limit the entry of many drugs into the brain?
-blood capillaries tightly joined
-blood capillaries covered by foot-like sheath arising from astrocytes
–> drug leaving capillaries in brain also have to traverse nonporous capillary cell wall + membrane of astrocyte to reach neuron
What areas of the brain have capillaries that are relatively permeable?
◼ Pituitary gland (
◼ Pineal gland
◼ Area postrema
◼ Median eminence
◼ Choroid plexus
What is choroid plexus in the brain for?
a structure in the ventricles of the
brain where cerebrospinal fluid is produced
What factors of a drug play important role in transporting it into the CNS?
lipid solubility, molecular size, and the ionic state of drugs and carriers
How are macronutrients, micronutrients and ions transported into the brain?
by specific carriers
What are some macronutrients that are transported to the brains?
glucose, amino acids, fatty acids, and lactate
What are some micronutrients that are transported to the brain?
vitamins B1, B2 and B6, biotin (vitamins B7), pantothenic acid
(vitamins B5) and ascorbic acid (vitamins C)
What are some ions that are transported to the brain?
calcium, potassium, magnesium, sodium, and bicarbonate
What is the characteristic of the membrane separating fetal blood from maternal blood in the placenta barrier?
lipid-soluble substances diffuse
readily but water-soluble substances either do not or diffuse poorly
–> resembles other membranes
Name 2 classes of drugs that can readily cross the blood-brain and placenta barriers
Anaesthetics and analgesics
What could be a side effect of overdose of morphine?
Morphine-induced respiratory depression
Lipophilic compounds (e.g., dietary components, environmental pollutants, drugs) are easily absorbed (e.g., via GI tract or lung), but are excreted poorly.
True or false
true
Lipophilic compounds are easily absorbed, is it the same case regarding their excretion?
No
tend to accumulate and induce toxicity unless mechanism to convert them to water-soluble derivatives
How does the metabolism of lipophilic compounds occur?
Biphasic
phase 1: oxidation
phase 2: conjugation
Can drugs go through phase 2 metabolism directly, without going through phase 1 metabolism?
Yes
What happens to drug after phase 1 metabolism?
the drug may be activated, unchanged, or most often,
inactivated
What happens to drug after phase 2 metabolism?
inactivated
