Lecture 4: Overview of Pharmacokinetics and Time Course of Drugs Flashcards
the 4 key pharmacological processes
absorption, distribution, metabolism & excretion
ADME is able to significantly impact how much drug reaches the target, which influences the ___ of the drug
magnitude
if a drug is given by the oral route, it must first be absorbed by the ___ before reaching systemic circulation
GI tract
t/f protein binding can influence how drugs move through the body
true some drugs are moved through the body unchanged, however, most are ___
ome drugs are moved through the body unchanged, however, most are ___
metabolized
what is the primary site of metabolism in the body?
liver
in the liver, drugs are converted to ____. what is the purpose of this?
more soluble compounds; for easier removal (excretion) from the body
considering pharmacokinetics processes, various __ and ___ have been developed to facilitate different therapeutic outcomes
routes of administration and formulations
many drugs are available in many formulations to allow__
wider use of agent
some drugs may have various formulations that are used for different __ and __
indications and purposes
if a drug is applied directly to the site where we want it to act, it is called ___ administration
local
when is local administration appropriate?
when target tissue is easily accessed
give 2 examples of organs that are typically receive local administration
skin and lungs
inhaled dosage forms for conditions such as asthma are unique because the drug concentration is highest in the ___, which is ideal
lungs
t/f inhaled drugs used for asthma are typically not easily absorbed through lung tissue and therefore have limited systemic effects
true
why is it ideal that asthma drugs don’t easily cross the membranes of the lungs?
reduces risk of off-target drug effects
t/f the trend of targeted drug therapy with limited systemic effects is applicable to topical treatments used for dermatologic conditions
true
the local administration route is designed to deliver drug to ___
where drug action is desired
give 2 examples of topical that are delivered locally
steroids and antibiotics
what is systemic delivery?
when drug is given and circulates around the body fairly extensively
give two routes of systemic administration
- enteral
2. parenteral
in enteral administration, drug is absorbed into the body through the ___
GI trcat
give 2 examples of enteral administration
oral and rectal
describe the path of Tylenol in the body
swallowed whole, dissolves in the stomach and absorbed in the small intestine
enteral administration involves the drug interacting with the ___ in some way before entering systemic circulation
GI tract
what is the most common enteral route?
oral
what makes the parenteral administration different from the enteral route?
skips the GI tract
in parenteral administration, drugs are delivered directly to the __
systemic circuit
give examples parenteral routes (7)
IV, SC, IM, epidural, transdermal, inhaled, intranasally
what is the most straight forward, fastest parenteral route? why?
IV; skips multiple steps / barriers, delivering straight to systemic circuit
give an example of drug that can be absorbed by inhalation and delivered systemically
nicotine
give an example of drug that can be delivered transdermally for systemic effects
nicotine patch
the drug formulation of a nicotine patch allows for what sort of drug delivery?
slow release to systemic circuit via skin
drugs must cross ___ to gain access to the systemic circuit
membranes
give 2 examples of exceptions to the “must cross membrane to reach target” rule
- Iv because directly systemic
2. local application bc already delivered to action site
what is the blood brain barrier?
extra barrier to limit of substances to the CNS
what membrane must be crossed in oral administration?
GI mucousal lining
what membrane must be crossed in transdermal administration?
skin
what membrane must be crossed in inhaled administration?
lung epithelium
in most cases, ___ is the first necessary step after administration
absorption
if you are designing a drug to target the CNS, what is an extra consideration?
it will also need to cross the blood brain barrier
lipophilic drugs can easily cross _____ membranes
epithelial
highly lipophilic drugs are no water soluble, therefore may ___ and end up not __
aggregate ; absorbing
hydrophilic drugs cross membranes by ____ or ___
passive difusión or transporters
t/f ionized molecules are not likely to cross the membrane passively
true
many drugs are weak __ /___
acids / bases
extent of ionization of weak acids/bases is determined by ___ of the compartment
pH
the __ properties are often the most important determinant of whether an agent will reach systemic circulation and its target
chemical
the __ changes along the length of the GI tract
intraluminal pH
t/f compounds that may be ionized in the stomach pH may be neural in the small intestine
true
what 2 components of the small intestine makes it the primary site of absorption?
- large surface area
2. neutral pH
what is a risk of the low pH of the stomach?
many drugs can be destroyed
once absorbed in the GI tract, drugs travel via the ___ before reaching the systemic circuit
hepatic portal vein
hepatic enzymes ___ drugs
metabolize
t/f only a fraction of orally administered drug reaches systemic circulation, reducing the bioavailability of the drug
true
the fraction of orally administered drug that reaches the systemic circuit is a property of the drug formulation called __
bioavailability
list 6 factors that reduce bioavailability
- first-pass metabolism
- metabolism by epithelial enzymes
- poor absorption of drug
- breakdown of drug in stomach
- P-glycoprotein pumps remove drugs from cells
- sequestration of drug in bile or tissue @ site of administration
drugs that inhaled are at risk of being metabolized by __
enzymes of the lung epithelial cells
bioavailability Is defined as
the fraction of administered drug reaching the systemic circuit
once the drug is absorbed into the blood, what is the next step?
distribution
what is distribution?
movement of drug from the blood to the tissues & extracellular spaces
what is a common tissue where drugs are distributed to?
adipose tissue
the extent of tissue distribution determines how much drug is available to ___
act on its target
define volume of distribution (Vd)
theoretical value used to describe the tissue distribution of drugs
what are 2 issues with drugs that preferentially distribute to accumulate in tissues like adipose?
- leads drug away from target
2. storage of drug in this region can have long-term effects as drug diffuses back to circulation
the volume of distribution is calculated as the ratio of ___ over __
total amount of drug in body (mg) over blood concentration of drug (mg/L)
the “apparent” volume of distribution gives an indication as to ___
whether the drug distributes extensively into the tissues
why is the volume of distribution commonly called the “apparent” volume of distribution?
Vd does not correspond to real volume of body fluid
the Vd can be experimentally determined by characterizing the ___ phase of a ___ graph
early distribution; drug concentration /time
can Vd of a drug change based on alterations in other pharmacokinetic properties?
no
can changes of body composition affect Vd?
yes
drugs that can distribute through total body water have a Vd of ~__L
42
give an example of a compound that can distribute through total body water and its Vd
ethanol, 40L
drugs that accumulate in the tissues typically have a Vd of ___
much greater than 42L
give an example of. drug that accumulates in the tissues and its Vd
propranolol, 400L
drugs that are restricted to the plasma volume have a Vd of __
much less than 42
give an example of a drug restricted to plasma volume and its Vd
biologics, 3L
the utility of apparent Vd is that we can predict___
where a drug may be going in the body
a 70Kg adult male has about ___L of total body fluid
42
___L is used as a benchmark to compare the distribution of drugs in different compartments of the body
42
drugs that bind excessively to plasma proteins have Vds of ___
much less than 42
give an example of a plasma protein that drugs often bind to
albumin
give an example of a drug that binds extensively to plasma proteins
warfarin
explain why the Vd is so low when drug is extensively bound to plasma proteins
its trapped in the vascular space, unable to freely distribute
t/f protein binding is freely reversible
true
if a patient is stable on a Warfarin dose, adding another medication may result in ___
displacement of warfarin from the plasma protein, resulting in more free drug, which can lead to adverse effects as warfarin is a very potent drug
some drugs may ____ distribute to specific tissues
preferentially
biphosphonates preferentially distribute to ___ through ___ interactions
bone marrow through ionic interaction
99% of total body fluoride is found in the ___ and ___
bones and teeth
fluorine integrates into the ___ of bones and teeth
enamel matrix
Amiodarone is an antiarrhythmic drug that contains a ___group that is unrelated to its activity, but because os it, accumulation in the ___ may cause adverse effects
iodine; thyroid
biphosphates and fluorine preferentially bind what mineral?
calcium
amiodarone is selectively taken up by the thyroid gland for the biosynthesis of ___
thyroid hormones
what are the characteristic of drugs that are filtered out of the blood into the urine?
small, polar, water-soluble
t/f small, polar, water-soluble drugs may be detected in urine sample “unchanged”
true
many drugs need to be ___ for effective excretion
modified
metabolism tends to make compounds more __
polar
the processes of drug excretion from the body are defined as drug ___
clearance
t/f depending on the properties of the drug, clearance may have several components and contributions from different organs
true
elimination is another term used to describe the process of removing drugs from the systemic circulation, where clearance is described as a ___ for a particular drug and elimination is described as the ___
constant parameter; rate of drug removal
for the most part, drugs in this course follow ___order kinetics where elimination is dependent on ___
first; concentration
what is the primary means to remove drug>?
urine
the process of the kidneys filtering drugs for excretion is called
renal excretion
t/f most drugs need to be modified in order to be more easily excreted
true
create/unmask polar functional groups by oxidation, hydrolysis, reduction are all characteristic of what phase of metabolism?
phase 1
conjugation, adding polar groups by glucoronidation or methylation are all characteristics of what phase of metabolism?
phase 2
biotransformation occurs most often in the ___ and uses a variety of ____ recations to make drugs more polar
liver; biotransformation
t/f drugs can undergo Phase 1 or Phase 2 metabolism, or both and not necessarily in order
true
what type of drug needs to be activated by biotransformation(metabolism?
pro-drugs
give an example of a pro-drug and the active form once biotransformed in the body
codeine; morphine
t/f the metabolites of a metabolite may also have activity, so it is important to consider all the active forms
true
phase 1 metabolism is largely carried out by the __ enzymes
cytochrome P450
phase 1 metabolism also involves CYP metabolism by isoenzymes such as ___, ___, ___ and ___
3A4, 2C9, 2C19, 2D6
what are the 2 key enzymes in phase 2 metabolism and what are they each responsible for?
- glucuronosyl transferases : create glucuronide conjugates
- glutathione transferases : make glutathione conjugates
other enzymes such as __ and ___ have important metabolic roles in the actions of drugs
oxidases and hydrogenases
what are neprhronns?
individual filtering units in the kidneys
nephrons use ___ and ___ to remove substance from the blood
passive discussion and transporters
give an example of a compound that is reabsorbed into the blood in the nephron
glucose
rate of renal excretion is determined by ____ and ___
glomerular filtration rate and drug concentration
t/f drugs bound to proteins are more easily filtered
false
what is renal excretion>
the passive or active transport of molecules from the blood to the urine
while renal excretion is the primary site of elimination, drugs can also be lost by __, ___, ___, and ___
bile, sweat, feces, expiration
___ is used to model the plasma concentrations of drugs and design their dosing regimen
quantitative pharmacokinetics
what are the 5 key parameters of quantitative pharmacokinetics?
- half life (t 1/2)
- Vd
- clearance Cl
- steady-state concentration (Css)
- bioavailability (F)
what is the half life?
time required for the concentration of the drug to drop by 50%
in first order kinetics, the proportion of drug ___ remains constant
cleared
with a single dose IV, the ___ increases rapidly, but begins to drop as the drug is __ and __
blood concentration; metabolized and excreted
what are the risks of administering a single dose IV?
in the beginning the dose can be in the toxic range and can quickly drop below therapeutic levels
administration by continuous IV prevents peaks and valleys in drug concentration by matching ____ to achieve steady state concentration within therapeutic range
drug clearance rate
the key to achieving steady state level is matching ___ to __
amount of drug in to amount of drug out
the drug ___ and ___ determine the steady state concentration that is achieved
dose administered and the half life
in single dose IV duration of effect is determined by __ and ___
therapeutic range and half life
in continuous IV, the ____ rate is determined to achieve equal drug in to drug out
infusion
____ dosing is the most common at-home dosing regimen
repeated oral
repeated oral dosing can achieve similar steady state blood concentrations to that of ___
continuous IV
oral dosing is delayed compared to IV due to __
time to be absorbed by intestine
duration of effect for oral dosing depends on __ and __
therapeutic range and half life
general rule of thumb is that steady state concentration isn’t achieved until after ___ half lives of the drug
5
if the dose is too high, or the interval is too short, drug blood levels may be __
toxic
if the dose is too low or the interval is too long , the drug blood levels may be ___
too low have an effect
____ doses “fill up” the volume of distribution
loading
a loading dose followed by ____ will get the blood concentrations into the therapeutic range faster
multiple maintenance
t/f even with a loading dose, it will still take about 5 half lives to reach steady state
true
define drug interaction
change in pharmacologic effect of a drug that results when given concurrently with another drug or food
the most known drug interactions are related to altered ___
pharmacokinetic parameters (ADME)
non-pharmacokinetic drug interactions include ___ and ___ type interactions
chemical incompatibility and pharmacodynamic
provide 2 causes of modulation of CYP enzymes
- drug / other compounds such as toxins, chemicals, and natural products
- altered expression of CYP, change in lifespan, or antagonism of binding sites
most drug interactions have been found to occur due to changes in drug ___
metabolism
drugs can influence the ___ capacity of CYP by acting as either ___ or ___
metabolic, inducers or inhibitors
what are the effects of CYP inducers?
increase metabolism resulting in faster excretion and lower blood concentration
CYP inducers can result in what adverse effects?
treatment failure and reoccurrence of symptoms
what are the effects CYP inhibitors?
prevent drug metabolism
what are the adverse effects of CYP inhibitors?
may cause drug to accumulate at toxic levels
give 2 examples of CYP inducers
St. John’s wort, and phenobarbital
give 2 examples of CYP inhibitors
ketoconazole and grapefruit juice
pharmacodynamic drug interactions occur when the ___ of different drugs interact
pharmacologic effects
t/f the synergistic effect of using multiple antihypertensives can be beneficial
true
t/f the combined effect of increasing NT levels with two different anti-depressants can be dangerous
true
using drug with opposite effects at the same receptor can result in ___ or ___
inadequate therapeutic response or worsening symptoms
chemical incompatibilities result when two drugs interact making one or both ___
inactive
give an example of two drugs with chemical incompatibilities
penicillin and amino glycoside antibiotics
