Exam 3: Basic of Pharmacokinetics I Flashcards
Histamine H2 receptor
-Type of receptor: This is a GPCR really only present significantly in the GI tract
• Stomach
• Small intestine
Its endogenous ligand is histamine
Histamine stimulates gastric acid production
Famotidine H2 receptor
It is a competitive antagonist for histamine
• It blocks histamine from binding, hence less acid is
produced
• It is used to treat GERD
H2 receptors are
transmembrane proteins
•A single peptide with seven membrane spanning regions.
•Ligand binding initiates release of GDP from G-protein subunits from the intracellular side and allows binding instead to GTP
•The result is an increase in activity of adenylyl cyclase.
•Response time: Slow with a duration of seconds to min
GABAa receptor
This is a ligand-gated ion channel expressed in the brain•Its endogenous ligand is gamma-aminobutyric acid (GABA)
•GABA is an inhibitory neurotransmitter
•When GABA binds, it allows chloride ions to pass
•This inhibits neurotransmission
•Response time: Rapid with a duration of milliseconds
Zolpidem is what
is a GABAa receptor agonist
- It binds allosterically to GABAA and helps GABA bind
•This inhibits neurotransmission above and beyond natural levels
•It is used to treat insomnia
GABAs is a protein with
five subunits (a,B, y’s) that are combined to yield a functional receptor
- It has two binding sites for its endogenous ligand GABA that effect Cl- passage through a central pore
- It has one allosteric binding site for benzodiazepines
Pharmacokinetics
What body does to drug
The relationship between dose and effect ( dose-concentration)
-ADME
Pharmacodynamics
What drug does to the body Concentration-effect -Receptor-Drug interactions - Cell signaling/2nd messenger -Receptor expression/gene regulation - Potency and Efficacy
Affinity
- usually expressed as the dissociation constant (Kd)
• KD=concentration of free drug at which half of the receptors are bound
• Concentration of free drug (D)
• Concentration of free receptors (R)
• Concentration of bound drug-receptors (DR)
• Expressed in molar units (µM, nM, pM)
A small/low Kd indicates
high affinity
Formula for finding Kd
Kd = [D][R] / [DR]
As we increase the drug concentration,
we increase the amount of receptor binding
More drug-bound receptor equates
to greater biological effect
Increase in dose results in
increase in plasma conc. which increases the response/effect
EC50
The drug conc. at which yields 50% maximal response
If the receptor has lower affinity for a drug
it will require more of that drug to bind to the same number of receptors
Potency
amount of drug (conc.) needed to produce a certain effect
Efficacy
maximal effect a drug produces regardless of dose
ED50
dose that is therapeutically effective in 50% of the population
TD50
Dose that causes toxic effects in 50% of the population
LD50
Dose that is lethal in 50% of the population (animal)
Therapeutic Index
Ratio between toxic dose and effective dose
• Therapeutic Index (TI) = TD50/ED50
Is it preferable to have:
A. a high therapeutic index or
B. a low therapeutic index?
A. a high therapeutic index
Absorption
Dissolution/liberation of drug from formulation
• Gastric emptying
• Passive/facilitated/active transport through intestinal wall
Metabolism
- Intestinal microbiota
- Enterocyte enzymes
- First pass effect
Distribution
- Highly perfused tissues - Blood, liver, kidney, heart, lungs
- Poorly perfused tissues - Fat, muscle, CSF
Excretion
Filtration/secretion into urine
• Biliary excretion
Cmax
Max observed plasma drug conc.
Tmax
Time it takes to reach Cmax
MTC
Maximum Therapeutic Concentration
MEC
Minimum Effective Concentration
MTC-MEC
Therapeutic window/range
Latency/ Onset of effect
How long it takes to get to Minimum Effective Concentration (MEC)
Serum
soluble components of blood obtained after clotting and centrifugation
Plasma
soluble components of blood, clotting factors are inactivated (i.e.-fibrinogen)
Buffy coat
WBCs and platelets
Whole blood
Consists of:
- WBCs
- RBCs
- platelets
- plasma proteins
- small molecules
- ions
- water
Concentration is
mass / volume
mass of drug = amount of drug (mg)
Volume (Units= L, mL and cc)
Blood volume
5 L
Plasma volume
Blood - cells = 2.5 L
Hemocrit
% of blood volume that cells take up
By what route of administration do we assume 100% absorption?
IV bolus
Soluble substances will partition more into
the plasma
Insoluble substances will partition/ go into
fat
Volume of distribution
Theoretical volume that the drug homogeneously distributes into
- How large of a volume is needed to account for the observed plasma concentration given
the introduced dose
Volume of distribution (Vd) formula
Vd = Amount of drug (mg) / [Conc] (mg/L)
Amount of drug absorbed on top
Plasma Conc. (C0, (mg/L))
- Assumes 100% absorption
Intravascular
within blood vessels
Plasma
fluid between RBCs and WBCs in the blood
Intracellular fluid
fluid within RBCs and WBCs
Extravascular
outside of blood vessels
Interstitial fluid
fluid between tissue cells in the extravascular space
Intracellular fluid
fluid within tissue cells
Body Composition
Fluids make up 60% of body weight
- Of this ~ 35% is intracellular fluid
Blood volume is 2x of plasma
Whole body has how many liters
40 L
If the drug is highly water soluble, it will be retained where?
- largely in the aqueous media of the body
- will have a higher plasma concentration and a low VD
If the drug is highly lipid soluble, it will partition into
tissues and fat, hence will have a lower plasma concentration and a high VD
A low Vd will have a
higher plasma conc.
A high Vd will have a
Low plasma conc. and will partition into the tissues and fats
• If the VD is very small, then the drug is largely present
in the intravascular fluid (plasma) only and doesn’t partition much into the intracellular fluids
If the VD is 18 L, then the drug is largely present
in the total extracellular fluids only and doesn’t
partition much into the intracellular fluids
If the VD is ~40 L, then the drug is largely present
in all body fluids and not in the tissues
Loading dose
Drug plasma conc. x Vd
- dose needed if we have the desired plasma conc. and the Vd
Characteristics of drugs in the blood
Drug distribute to organs, but it also can distribute to cells within whole blood
- A drug is twice as concentrated in the plasma
Drug conc. in the plasma
Plasma conc. may not be the same as Blood conc.
Blood: Plasma ratio
Ratio of conc. of drug in whole blood (cells + plasma) versus that in the plasma only
Plasma proteins reside in the plasma – not in the cellular components
Chloroquine
its an anti-malarial
- it partitions into and is sequestered by RBCs leaving less drug in the plasma
- Yields a blood: plasma ratio greater than 1:1
Warfarin
- is an anti-coagulant agent
• Prevents oxidized vitamin K from becoming reduced
• Prevents formation of clotting proteins
• Warfarin is highly plasma protein bound
• It remains sequestered in the plasma
• This would yield a blood:plasma ratio <1:1
Intracellular fluid has what volume
24.5L- volume
35%
Extracellular fluid
18 L-volume
25%
Interstitial fluid is what % of body
21%-volume
Plasma
4%
2.5 L- Volume
