pharmacokinetics Flashcards
4 Principles of Pharmacokinetics
Absorption
Distribution
Metabolism
Elimination
Variable affecting absorption
bioavailability
variable affecting distribution
volume of distribution
variable affecting metabolism
half-life
variable affecting elimination
clearance
Bioavailability (F) Definition
the fraction of unchanged (still active) drug that reaches the systemic circulation
F = 100% when:
the drug is administered directly into a patient’s blood vessels
- IV, IA, PICC
F < 100% when:
some of the drug is lost before reaching the heart
How can F < 100%?
a. some of the drug is lost before instestinal absorption
b. lost by modification of the drug by intestinal/ hepatic metabolism (enzymes)
c. lost because transporters return the drug to the gastrointestinal tract (into bile, SI)
How is bioavailability calculated?
by comparing the amount of drug absorbed over time from the route of administration of interest to the amount of drug absorbed over time when the same dose is giver by the IV route
the Area Under the Curve (AUC) is directly proportional to:
the dose administered and the bioavailability of the drug
A large curve (AUC) =
a large dose
slow clearance
a large dose =
a large area under the curve (AUC)
a small area under the curve (AUC) =
a small dose
fast clearance
a small dose =
a small area under the curve (AUC)
AUC is inversely proportional to:
the clearance of the drug
fast clearance of the drug =
small area under the curve (AUC)
slow clearance of the drug =
large area under the curve (AUC)
Factors affecting bioavailability: (5)
- Gastrointestinal System Motility
- Gastrointestinal Surface Area
- Hepatic Metabolism
- pH of liquid surrounding the drug
- Drug Interactions
Factors affecting bioavailability: Gastrointestinal System Motility
a. rate of gastric (stomach) emptying
b. rate of intestinal emptying (intestinal motility)
Slow gastric emptying =
reduced bioavailability of the drug
- reduced SA in stomach for
absorption
- destruction by low pH in
stomach + gastric enzymes
Fast gastric emptying
increased bioavailability of the drug
- less time in stomach
subjected to low pH + gastric
enzymes
- moves to an area with
increased SA for absorption
Low intestinal motility (stasis) =
increased bioavailability
- more time to interact with SA
and be absorbed
- low pH, not destroyed
Fast intestinal motility (diarrhea) =
reduced bioavailability
- less time to interact with SA
and be absorbed
- often discarded in full, no time
to reach therapeutic
minimum
Factors affecting bioavailability: Gastrointestinal SA
a. greater SA for absorption in intestines than stomach
Increased gastrointestinal SA =
increased bioavailability
- no inflammation
- no resection of the intestines
- intact brush boarder enzymes
Decreased gastrointestinal SA =
decreased bioavailability
- inflammation
- resection of the intestines
- decreases brush boarder
enzymes, unable to break
down drug for use
Factors affecting bioavailability: Hepatic Metabolism
a. enzymatic activity
b. anatomical or chemicals
inhibiting hepatic function
Increased enzymatic activity (hepatic metabolism) =
normal drugs = decreased bioavailability
- body inactivates more drug
pro drugs = increased bioavailability
- body activates more drug
Decreased Enzymatic activity (hepatic metabolism) =
normal drugs = increased bioavailability
- body inactivates less = accumulation
pro drugs = decreased bioavailability
- body is unable to activate
drug to exert its effects
occurs in cases of liver failure, liver disease, or chemicals inhibiting hepatic metabolism
Importance of hepatic metabolism
some drugs rely on hepatic metabolism working to decrease bioavailability
- ex: nitroglycerine is 90% destroyed by the liver –> if less is destroyed, the risk of overdose increases
Factors affecting bioavailability: pH of liquid surrounding the drug
pH can influence the chamical stability of a drug and influence it’s charge
- the drug’s charge will affect its lipid solubility and how readily it can pass through cell membranes to be absorbed (charged drugs cannot be absorped)
Weak acids become HA in:
acidic liquids
HA (properties)
- neutrally charged, easily absorbable
- become neutral in acidic liquids
Weak acids become A in:
basic liquids
A +/- (properties)
- charged, not readily absorbable
- become charged in basic liquids
Weak bases become BH in:
acidic liquids
BH (properties)
- charged, not easily absorbed
- become BH in acidic liquids
Weak bases become B in:
basic liquids
B (properties)
- neutral charge, can be absorbed easily
- become B in basic liquids
Factors affecting bioavailability: Interactions between two drugs
can cause the drugs to precipitate and form crystals
* crystals cannot be absorbed
precipitation = decreased bioavailability
no precipitation - increased bioavailability
Factors affecting bioavailability: Interactions between food and drugs
the presence of food can affect the pH of the liquid in which the rug is found and change its charge
–> greater when drug is administered during or shortly after ingestion
Distribution Definition
following absorption, a drug is distributed via the circulatory system towards the cells in the body
Factors affecting distribution
a. lipid solubility of the drug (charge)
b. binding of drug to plasma proteins/ accumulation in tissues
c. blood flow to organs/ relative organ size
Factors affecting distribution: blood flow + organ size
more important tissues/ organs have a greater blood supply relative to size –> increased/ faster absorption
less important tissues/ organs have a smaller blood supply relative to size –> decreased/ slower absorption
Organs with rapid distribution:
kidney, liver, heart, lungs, brain
Organs with slow distribution:
fat, skin, bone, teeth
Volume of Distribution
the volume of the pool of bodily liquid required to account for the observed drug concentration initially measured in the body
-> volume of liquid in body that
the dose is being distributed
into
what is Vd directly proportional to?
half-life
what is Vd indirectly proportional to?
clearancce
an increased Vd =
increased half-life
decreased clearance
a decreased Vd =
decreased half-life
increased clearance
Vd equation
Vd = amount in body/ plasma concentration
dose equation
dose (average) = concentration (therapeutic) x Vd
If a drug is highly bound to plasma proteins:
drug concentration in plasma is high
Vd is small
- plasma proteins cannot leave blood
vessels, so the space in which the
volume is distributed to is low
If a drug is NOT highly bound to plasma proteins:
drug concentration in plasma is low
Vd is large
- more space to distribute the volume to
Interactions of plasma proteins with drugs are:
a) high capacity
b) low affinity
What kind of drug can leave the blood vessels? (bound or unbound)
only unbound drugs can leave the blood vessels
Does a drug that is highly bound (99%) to plasma proteins necessarily demonstrate low pharmacological activity?
no - even the 1% that is unbound is enough to interact with its target receptor and have an effect
Does a drug that is 100% bound to plasma proteins demonstrate low pharmacological activity?
yes - there is no unbound drug available to leave the blood vessels to interact with its target receptor and have an effect
When are drug-drug interactions affecting the binding of plasma proteins of other drugs clinically relevant (concerning)?
a. the initial drug is high bound to plasma proteins (80% +)
b. the therapeutic index of the bound drug is narrow
b. the effectiveness of eliminations is reduced
Therapeutic window
the ratio comparing the lethal dose in 50% of the population and the effective dose in 50% of the population
- index provides an indication of the
relative margin of safety available when
using the drug
Why are drug-drug interactions concerning if the initial drug is highly bound to plasma proteins?
the initial drug has to compete for its spot
–> increased risk for excess to be
released into blood stream than
intended
Why are drug-drug interactions concerning when the therapeutic index of the bound drug is narrow?
the window between the dose that is therapeutic and legal is very small
–> increased risk that too much or
too little drug will become unbound
(less control over effect)
Why are drug-drug interactions concerning when the effectiveness of elimination systems is reduced?
the body has a reduced ability to excrete excess drug, causing more to accumulate and continue to exert effects
–> increased risk of drug concentration
reaching lethal dose
what drug tends to accumulate in bone?
tetracycline
where does tetracycline tend to accumulate?
bone
what drug tends to accumulate in the liver?
cloroquine
where does chloroquine tend to accumulate?
liver
what drug tends to accumulate in adipose tissue?
insecticides
where do insecticides tend to accumulate?
adipose tissue
what are circumventricular organs?
areas of the brain that are “leaky”, allowing contact between the blood and specialized neurons
what is the blood brain barrier?
tight junctions in the blood vessels in the brain that do not permit drugs to filter through gaps in cells (like the rest of the body)
what drugs can pass the blood brain barrier
lipid-soluble, uncharged –> passive diffusion
non lipid-soluble, charged –> transport proteins (specialized, when present)
how can drugs pass through the blood brain barrier?
THROUGH cells –> passive diffusion
THROUGH cells –> transport proteins
Goal of Metabolism
to convert the drug into highly charged, sometimes inactive, mostly water soluble compounds that can be readily excreted by the liver
Where are drugs metabolized? (4 organs)
Liver, Intestines, Kidneys, Lungs
What organ metabolizes the majority of drugs?
The Liver
Metabolism Phase 1
addition of reactive group to drug (-OH, -NH2)
–> drug may be activated, inactivated, or
unchanged
Metabolism Phase 2
Conjugation (addition) of a reactive group with a highly charged, soluble substrate
–> conjugated is usually inactive
what is the most common charged, water soluble substrate attached to reactive group in phase 2 of metablolism?
glucuronic acid
what is it called when glucuronic acid is conjugated to the reactive group in phase 2 of metabolism?
glucuronidation
What does metabolism do to normal drugs?
Inactivates
What does metabolism do to prodrugs?
Activates
Effect of increased metabolism on normal drugs
decreased therapeutic effect/bioavailability –> increased drug inactivation
Effect of increased metabolism on prodrugs
increased therapeutic effect/bioavailability –> increased drug activation (accumulation)
Effect of decreased metabolism on normal drugs
increased therapeutic effect/bioavailability –> decreased drug inactivation (accumulation)
Effect of decreased metabolism on prodrugs
decreased therapeutic effect/bioavailability –> decreased drug activation (cannot exert effect)
effect of inducers on metabolism
increases the action of CYP
effect of inhibitors on metabolism
decreases the action of CYP
effect of inducers on normal drugs
decreases therapeutic effect/bioavailability –> increases inactivation of drug
effect of inducers on prodrugs
increases therapeutic effect/bioavailability –> increases activation of drugs
effect of inhibitors on normal drugs
increases therapeutic effect/bioavailability –> inactivates less drugs (accumulation)
effect of inhibitors of prodrugs
decreases therapeutic effect/bioavailability –> activates less drugs
what is the most abundant cytochrome P450?
CYP 3A4
where is CYP 3A4 found?
the liver, intestinal wall
what inducer acts on cigarette smoke?
CYP 1A2
what inducer acts on phenytoin?
CYP 3A4
what inducer acts on rifampin
CYP 2C9
what inhibitor acts on ketoconazole
CYP 3A4
what inhibitor acts on erythromycin
CYP 3A4
what inhibitor acts of grapefruit juice?
CYP 3A4
CYP 1A2 acts on:
cigarette smoke (inducer)
CYP 2C9 acts on:
rifampin (inducer)
CYP 3A4 acts on:
phenytoin (inducer)
ketoconazole (inhibitor)
erythromycin (inhibitor)
grapefruit juice (inhibitor)
inducers usually exert effects after ___ exposure
chronic (repeated) exposure
inhibitors usually exert effects after ___ exposure
acute (single) exposure
sources of elimination (5)
- urine
- feces
- milk
- sweat
- expired air
enterohepatic circulation
drug enters the bile from the liver, is secreted into the gut with bile, then is reabsorbed into bile by the liver
–> cycle repeats and drug is stuck in loop,
cannot exert therapeutic effect
filtration at the level of the kidney: charged drugs
cannot be actively secreted or reabsorbed in the kidney –> eliminated via urine
filtration at the level of the kidney: uncharged drugs
can be actively secreted and/or reabsorbed in the kidney
filtration at the level of the kidney: bound drugs
cannot be filtered into the glomerulus –> stay in blood stream
filtration at the level of the kidney: free drugs
can be freely filtered into the glomerulus –> can leave bloodstream
half-life
the time required to reduce the drug plasma concentration by 50%
–> independent of dose, fixed value
95% of drug plasma concentration is eliminated after ___ half lives
4-5 half-lives
Concentration Steady State (CSS)
if a drug is repeatedly administered before the previous dose is completely eliminated, drug levels will accumulate with time
–> absorption = elimination
how many half-lives until concentration steady-state is reached?
4-5 half lives
magnitude of CSS is directly proportional to:
dose/ bioavailability
magnitude of CSS is indirectly proportional to:
half-life or clearance
increased CSS magnitude =
decreased half life/ clearance
increased dose/ bioavailability
decreased CSS magnitude =
increased half-life or clearance
decreased dose/ bioavailability
CSS is independent of:
dose
magnitude of CSS is dependent on
dose
CSS is dependent on:
administration timing
loading dose
an immediate, large dose of medication to keep plasma drug concentration above therapeutic level until natural CSS is reached
–> will slowly leave the body as plasma concentrations of taken drug rises
CSS equation
CSS = dose/ clearance
what drugs do not have a fixed half-life?
some anti-convulsant drugs, phenytoin
