LS5003 TB1 (Dr Piper) Flashcards
define drug disposition
disposition refers to what happens to the drug after it enters the body,
(i.e. excluding absorption)
wht is the abbreviation used for drug diposition
Administration
Distribution
Metabolism
Eexcretion
define bioavailiability (F)
the fraction(F) of administered dose that reaches the systemic circulation
what F value does intravenous injection give
1 (100%)
what does BioA mean
bioavailability = the measure of the fraction of an administered drug which reaches systemic cirulation
define pharmacokinetics
the way the body affects the drug
define clearance
how much is being removed from the body per unit of time
define pharmacodynamics
the way the drug affects the body
what does pharmacokinetics consist of?
.absortion .metabolism .distribution .excretion
how is the therapeutic (window) index calculated
TD50 / ED50
define ED50
Effective dose producing 50% response in population
define TD50
toxic dose in 50% of population
with therapuetic index, is bigger better or worse?
better
there are also no units
define therapeutic index
a measure of its selectivity in producing theraputic effects rather than unwanted effects
give the units for
milli
micro
nano
pico
femto
m 10-3
u 10-6
n 10-9
p 10-12
f 10-15
whats avagadros constant
6 x 1023 atoms/molecules
define molarity (M)
number of moles of a substance dissolved in 1 litre of water
convert 2uM to pM
2uM = 2,000,000pM
what are agonists
any drug (or exogenous/endogenous substance) that binds to a receptor and activates it to cause a response
define Kd
drug conc reaquired for 50% receptor occupancy
Bmax
100% receptor occupancy
define EC50
effective conc causing 50% of max effect
Emax
maximum effect a drug can have either in a tissue/ organ/ whole organism
drug efficiancy
maximum effect a drug can produce regardless of the dose i.e. max effect achievable
drug potency
the concentration of drug needed to produce a given effect
e.g. increase heart rate by 5 beats per minute
why could EC50 and Kd be different in some tissues
- we dont know how muc of a drug dose actually reaches the receptors (some could be degraded by the body/ taken up by other tissues)
- there may be ‘spare receptors’ in tissues
do ‘spare receptors’ differ strucurally?
no, structurally identical
they are just an excess
how could you tell if there spare receptors (2 ways)
EC50 usually lower than Kd
adding an irreversible antagonist i.e. blocking a proportion of the receptors does not always affect he max response
fill in this diagram
whats meant by drug translocation
movement of a drug into circulation
drug absorbtion can be described in terms of
rate and extent
list the 4 principle mechanisms of drug translocation
1) diffusion through lipid
2) diffusion through aqueous channel
3) carrier
4) endocytosis
in diffusion through lipids
- do most drugs diffuse this way
- what drugs can?
- dependent on what?
- yes most drugs so diffuse this way
- only small lipid soluble, non-polar/ non-ionised drugs
- dependent on S/A and blood flow
what law corresponds to diffusion through a lipid layer
fick’s law
whats the criteria for rapid permeation (lipid diffusion)?
and what are these two criterias mesured by?
which of these are most important in lipid diffusion?
- drug molecules must be presetn in membrane in sufficient numbers (partition coefficient)
- drug molecules must be mobile within the membrane (diffusion coeficient)
Partition coefficient = most important for lipid diffusion
partition coefficiernt =
ammount of drug in lipid phase / ammount of drug in aqueous phase
in diffusion through aqueous pores/ion channels
- how does it move
- what molecules can travel this way
- 2 examples
- is it a common mechansim for drugs
- high to low conc
- small water soluble molecules of less than 100 Da
- lithium (bipolar disorder), radioactive iodide (thyroid overactive)
- no, not major route for drug permeation
what are the 2 types of carrier mediated transport?
how do these differ?
what important sites contin these mechansims
active transport and facilitated diffusion
active= ATP required as agaisnt conc gradient facilliated = no ATP required
renal tubule, blood-brain barrier, GI tract
what are the 2 types of solute carrier transporters (SLCs), give 1 example of a drug that uses these
- organic anion transporter (OAT), antibiotics
- organic cation transporter (OCT), quinine, cisplatin. cimetdidine
what are the active trasnpot mechanisms ofter reffered to as?
give 2 examples of drugs recognised by these mechanisms
ATP-binding cassette (ABC) transporter
digoxin, quinidine
name a drug that utilised the carrier mediated transport mechanisms for
facilitated diffusion: -
active transport: -, -
facilitated: L-dopa used in parkinsons disease
active: penicillin in renal tubule, 5-fluoruracil (anticancer drug)
endocytosis normally concerned in the uptake of what molecules?
what types of drugs can permeate via this route?
example:?
attempts to utilise it as targeted drug uptake mechanism?
- macromolecules
- large molecular weight (1000Da or more)
- insulin crossing blood brain barrier
- incorporating the drug into lipid lipsomes
name the 6 physiochemical factors affecting drug absorbtion
- molecular weight
- particle size
- physical nature of drug
- drug partition coefficient
- salt form of drug
- polymorphism and amorphism
when does molecular weight affect drug absorbtion?
when drug is absorbed via passive diffusion
define micronisation
process that helps reduce particle size to that in the range of micrometes or nanometers improving absortion of poorly soluble drugs
the physical nature of drugs is that most drugs are weak acids or bases. Therefore will exhibit ?
are ionised species lipid soluble?
pH dependent ionisation
No
define pKA
ionisation constant, equal to pH at which 50% of drug is ionised
Write the ionisation equations for weak acids and bases and state which sides of the equation are ionised and which are non-ionised
state the henderson-hasselbach equations for both weak acids and weak bases
define lipinski’s rule of 5
rule of thumb that describes the “drugablilty” of a molecule.
determines if molecule has the chemical and pjysical porperties that allow it to be orally active.
What are the 4 categories of lipinkis rule of 5
1) molecular weight under 500Da
2) Octantol: water partition coefficient (logP) that does not exceed 5
3) no more than 5 hydrogen donors
4) no more than 10 hydrogen acceptors
name the 5 compartments the body can be visualised as which the drug can distrubute into, including their % of body weight they make up:
- plasma (5%)
- interstitial fluid (16%)
- intracellular fluid (35%)
- transcellular fluid (2%)
- Fat (20%)
based in a 70kg person, what are the average litres of each of these fluids:
- plasma
- intracellular
- interstitial water
- extracellular water
- total body
- 3L
- 27L
- 12L
- 15L
- 42L
define Vd
the volume of plasma that would contain the total body drug content at a concentration equal to plasma concentration
whats the equation for Vd?
Vd = D / Cp
what does the Vd value indicate?
where the drug is most likely to be distributed in the body
any drug with a Vd of over around 50-60L indicates what?
tissue binding
what will tissue binding do to the apparant concentration in Vd calculations
artificially lower the concentration to less than expected due to drug binding to tissue
what 2 factors effect the rate of distribution
rate: -membrane permability
- blood perfusion
what factors effect the extent of distribution:
- lipid solubility
- degree of ionisation
- plasma protein binding
- intracellular binding
what 2 factors effect membrane permeability:
- dependent on charcteristics of the organ membrane
- membranes have varying pore size
at therapeutic concentrations most drugs show binding to plasma proteins. what percentage of drug tends to bind to plasma proteins
99% bound,, 1% free
drug binding to plasma proteins
total drug =
bound drug (Fb) + free drug (Fu)
the amount of binding to plasma proteins is dependent on what factors?
- free drug conc
- affinity of the drug for the binding site
- plasma protein conc
in the case of plasma proteins (albumin) how many binding sites to which the drug can bind do they typically have?
1-4 sites
what is the dispositional signifcance of binding?
- allows transport of more drug than would be predicted from its aqueous solubility (plasma)
- acts as a reservoir (compartments) which helps to prolong the action of drugs
- however only drug which is not bound to plasma protein can produce pharmaclogical effect
- bound drug cannot pass membranes
what types of drug can pass from the mother to the foetus?
-lipid soluble drgs
what placental characteristics can determine drug transfer
- placental bloodflow
- placental transport machanisms
- placental metabolism
how does foetal plasma preotein levels differ form the mother?
albumin is more concentrated
how does foetal blood pH differ from maternal blood pH
foetal blood has a lower pH
what are the 6 things that influence rate and extent of distribution
- membrane permeability
- blood perfusion
- lipid solubility
- degree of ionisation
- plasma protein binding
- intracellular binding
what is biotransformation?
few drugs are eliminated from the body unchanged. most undergo biotransformation. this means a chemical modification inside an organism, usually turning non-polar molecules polar to stop reabsortion in the renal tubules, allowing excretion.
what are the sites of metabolism for drugs;
- liver
- kidney
- lungs
- skin
- intestine
what is the primary process of metabolism
However in certain instaces:
1) drugs can be?
2) metabolism can produce?
to change a drug into more water soluble molecules (increases polarity to aid excretion)
1) drugs can be activated by metabolism. These are termed pro-drugs
2) metabolism can produce more active metabolites which contribute to the action of the drug
what are pro-drugs?
give an example?
A prodrug is a medication or compound that, after administration, is metabolized into a pharmacologically active drug.
e.g. L-dopa
what are phase 1 metabolism reactions
- parent drug is converted into a more polar molecule
- achieved by either introduction of or unmasking of a polar functional group
what are phase 2 reactions
- involves conjugation reactions
- occur ar polar groups introduced/unmasked during phase 1 reactions
- reactions tend to produce an inactive and very water soluble moelcules
- excretion then follows, mainly by the renal route
are metabolism phase 1 reactions catabolic or anabolic
catabolic
what are the 5 types of phase 1 reactions
aromatic hydroxylation
hydroxylation
dealkylation
deamination
desulphuration
what is the most important enzyme for metabolic reactions
microsomal miced function oxidase
what is cytochrome P450 and what does it do
- a haem protein
- forms part of electron transfer system
- binds: molecular oxygen, substrate (ie parent drug)
- exists in many isoforms with different substrate specificity
name the 3 non microsomal mixed function oxidase phase 1 reactions
A.oxidative reactions
B.reductive reactions
C.Hydrolytic reactions
Phase 2 reactions occur mainly where?
-liver
what type of reaction are phase 2 reactions, and where on the molecule do they occur
conjugation reactions which occur at polar groups
what is the most common phase 2 conjugation reaction?
glucoronidation
whats meant by first pass metabolism
metabolism of drug before it reaches systemic cirulation
sites of first pass metabolism
liver
intestinal wall
whats extraction ratio
whats the formula for it
measure of hepatic clearance
CLliver / Q
Q = hepatic blood flow
Drug interactions, in drug metabolism, can occur via what 2 mechanisms
enzyme induction
enzyme inhibition
