Principles of Pharmacokinetics Flashcards
Any proposed pharmacological therapy, no matter how promising, will fail in clinical trials if
the ddrug is unable to reach its target organ(s)
at concentrations sufficient to have a therapeutic effect
what makes a drug successful
A successful drug must be able to cross the same physiologic barriers that exist in the body to limit access to foreign substances (e.g., virus, bacteria, and environmental toxins)
what is pharmacokinetic
study of how drugs are acted upon by physiological functions
essentially what the body does with the drug
describe the overview movement of drugs
a drug enters the body, circulates thorugh body, changed by the body, leaves the body
what are the 4 major steps of drug movement in the body and time course
AD & ME
Absorption - input
Distribution - drug in tissues; highway (plasma, blood supply, etc.)
Metabolism (biotransformation) - metabolizes to be eliminated from the body
Excretion (elimination) - output; drug is eliminated through urine, bile, feces, breath etc.
describe drug absorption
can occur by a number of mechanisms designed to either exploit or breach the body’s physiologic barriers
Method of drug administration greatly affects its absorption
Method of drug administration does not affect its absorption
false
it does
describe drug distribution
Following absorption, the drug will utilize the body’s distribution systems such as blood and lymphatic vessels to reach its target in an appropriate concentration
The ability of the drug to access its target site also is limited by several patient processes
These processes fall broadly into two categories
drug metabolism
drug excretion
describe drug metabolism
The body inactivates the drug through enzyme degradation especially in the liver
describe drug excretion
After being metabolized, the drug is excreted out of the body
Primarily through the kidneys (urine), liver (bile), and gut (feces)
enteral route
Drugs given by this route are placed directly into the gastrointestinal tract and includes
oral administration
rectal administration
topical route
Drugs applied to the surface of body and includes
transdermal administration (skin patches or ointments)
otic - ear drops
nasal - nose drops
opthalmic - eye drops
topical
applied on the surface
ex: ct scan with contrast etc.
only stays on the skin and the skin layers
transdermal
applied on the skin as well (patches)
but penetrates through the skin layer to effect on more distant parts
routes of drug administration
oral
sublingual - tongue
buccal -cheek or into jaw
transdermal - topical
injection
intranasal
ophthalmic
otic
benefit and limitation of enteral route
simplest of all routes
Ease of self administration; no skilled medical care needed
Very portable
Less likely to introduce systemic infections unlike parenteral route
route does expose the drug to harsh environments
Lipid soluble drugs pass through the GI tract most easily
Food in the stomach may or may not alter the rate of absorption
pH of the stomach and drug may interfere with drug absorption
Presence of other drugs in the stomach may cause a drug interaction (in the oral route)
Drugs go through a first-pass metabolism in the liver
describe the purpose of drug development
whole purpose of designing a drug is going to the correct receptor with the correct dosage and some are better favored to go one route than another
injection vs pill form of a drug
injection - effect very quickly in s
pill- takes longer 30-40 min
what is first pass metabolism in the liver
process by which a drug’s concentration is significantly reduced before it reaches the systemic circulation. This process occurs mainly in the liver and sometimes in the intestines after the drug is absorbed from the gastrointestinal tract.
Drugs that are administered orally pass from the GI tract to the portal veins and enter the liver before entering the systemic circulation
This system protects individuals from the effect of ingested toxins, which are detoxified in the liver
checkpoint
liver
checking for any toxins
can parts of the drug cause damage to the body
Any drug that exhibits first-pass metabolism must have appropriate dosage to ensure effective concentration on target organs because of some inactivation in the liver
true
Non-enteral routes of administration are subject to the first-pass metabolism by the liver
FALSE
pill form dosage will always be higher than injection form
true
90% of oral medication is metabolized and destroyed by the liver before it gets to the heart
true
steps of first pass metabolism
oral med sits in stomach for 30-45 min
portal circulation: blood from intestines goes to liver for detoxification
liver: metabolizes 90% of oral meds
benefits of parenteral administration
intravenous (IV) administered drug is immediately available in the circulation
intramuscular (IM) or subcutaneous (SC) administration has a slower entry into the circulation than I/V but faster than enteral administration
fast onset of drug action
bioavailability of drug is 100%
IV - more controlled delivery; continuous meds
one injection can last days to months
The amount of drug reaching the system will be the same for all routes of parental administration
true
non-intravenous parental routes will take longer for the drug to reach peak values in the circulation
true
IV onset
15 - 30 s
IM & SC onset
3-5 mins
routes used for oil-based drus
IM & SC
drugs too irritant for the drug and administered parenteral
chemotherapeutic drugs
disadvantages to parenteral administration
Greater risk of addiction with drugs that are injected as the onset of action is very rapid
Not practical for patients who cannot self administer injections
Belonephobia (fear of needles and injections) limits this route
High risk for hepatitis, HIV, etc., if needles are shared
Most dangerous route of administration as it bypasses all the body’s natural defenses, including the BBB if given intrathecally, exposing patients to death from adverse reactions or health problems
Potentially fatal air bubbles (especially IV) can be introduced
Strict asepsis is required
Requires trained/skilled personnel; cost is generally much higher
Most dangerous route of administration as it bypasses all the body’s natural defenses, including the BBB if given intrathecally, exposing patients to death from adverse reactions or health problems such as
HIV, hepatitis, abscess, infections, drug additibes/contaminants
why is parenteral administration the most dangerous rourte?
because it bypasses the BBB and bypassing the body’s defenses
what is bioavailability
subcategory of drug absorption
how much of drug you took and how much of it is available
amount of drug available in the circulation
how is bioavailability quantitatibely defined
bioavailability = Quantity of drug reaching systemic circulation ÷ Quantity of drug administered
I/V drugs are injected directly into
systemic circulation
drugs administered orally have a bioavailability of
< 1 primarily
drugs administered by IV have bioavailability of
generally 1 (maximum)
what is bioavailability dependent on
route of administration
chemical form of the drug
patient factors like gastrointestinal enzymes & pH and hepatic metabolism
Concept of bioavailability becomes important with generic drugs
have the same molecule structure, but concentration and route of administration may differ
Drugs soluble in aqueous solutions at physiologic pH often can be administered
orally
FDA mandates generics must have _______ of the bioavailabilityy of the parent compound
90%
After a drug is absorbed from its site of administration, it is distributed to its site of action primarily by the circulatory system (the blood plasma) and to a minor degree by the lymphatic system
true
why is the concentration of drugs in plasma is often used to determine therapeutic drug levels
because amount of drug actually taken up by target organs is difficult to measure
plasma concentration of a drug correlates well with the effect of the drug on its target site
true
what affects drug concentration in the plasma
Distribution of the drug in various tissues and compartments as well as blood flow variability between different organs affects drug concentration in the plasma
liver and kidneys usually receive the most blood flow
what usually receives the most blood flow
liver and kidneys
Drugs occur in two forms in the blood
Bound to plasma proteins, most commonly albumin
“Free” or unbound drug
This is the active part of the drug
what is the active part of the drug
“Free” or unbound drug
car example for drug distribution
you sittin in the car, car going on the highway
you are the drug, car is the protein, highway is the blood
once the car and you go to the destination you decouple from the car (cannot bring car into the classroom)
one that leaves the car (protein) unbound = bring about the change
one that stays in the car (protein) bound = no action brought about
free vs bound drug
one that leaves the car (protein) unbound = bring about the change
one that stays in the car (protein) bound = no action brought about
most abundant protein in the body
albumin
Ratio of bound:unbound drug remains the same in the blood
true
unbound drug from protein
brings about the change
Exerts desired effect on target drug receptor sites in the target organ(s)
bound drug to proteins
no action is brought
Remains in the compartment (vasculature) longer
A drug that exhibits high level of protein binding requires a higher concentration
The processes by which biochemical (enzymatic) reactions alter within the body are collectively called
drug metabolism or drug biotransformation
waht happens in drug metabolism
reactions convert lipid soluble drugs to water soluble metabolites so that the drugs can be more easily excreted by the kidneys
contains the greatest quantity and diversity of metabolic enzymes
liver
drug metabolism aso happens in
kidneys, lungs, nerves, skin, plasma & GI Tract
where does most of drug metabolism happen
liver
Biotransformation reactions are classified as
Oxidation/Reduction or Phase I
Conjugation/Hydrolysis or Phase II reactions
difference between phase I and first pass metabolism
first phase of metabolism in the liver
after drug has exerted its effect and gone to receptor organs and now it is taken out of the body here and happens for all types of route of administer
what is first pass metabolism?
happens in the liver but happens with oral meds and it detoxifies it and happens before it goes into the blood stream
before the drug goes to the receptor organs and only happens for the oral route
location is the same but function and ____ are different
they both happen in the liver
describe oxidation reduction (phase I)
exchange of ions
Phase 1 reactions modify the chemical structure of a drug through oxidation/reduction
The liver has enzymes that facilitate these reactions
most common pathway in the liver is the cytochrome P450 system (CYP pronounced “sip” enzymes) that mediates oxidative reactions
Some drugs are administered in an inactive prodrug form so that they can be metabolically altered in the liver to the activated form
This prodrug strategy helps to
most common pathway in the liver
cytochrome P450 system (CYP pronounced “sip” enzymes) that mediates oxidative reactions
drugs are administered in an inactive ______ form so that they can be metabolically altered in the liver to the activated form
prodrug
prodrug strategy helps to
facilitate oral bioavailability
decrease GI toxicity
prolong elimination of ½ life of a drug
what is 1/2 life of a drug
time it takes for the concentration of the drug in the bloodstream or body to reduce by half.
if a drug has a half-life of 4 hours, and you take a dose of 100 mg, after 4 hours, _____ mg of the drug will remain in your body.
After another 4 hours, _____ mg will remain, and so on
50
25
primary machine for metabolizing drug
cyp enzymes
involved in metabolism of about 75% of all drugs used today
cytochrome P450 (CYP) enzymes
more CYP = faster drug metabolism
less CYP = slower drug metabolism
true
If cytochrome P450 liver enzymes (CYP enzymes) are induced,
if you increase enzyme you increase metoblism (more breakdown) and drug leaves the body faster
If cytochrome P450 liver enzymes are inhibited, it
if there is less of the enzye there is less breakdown so it stays longer in the body
If cytochrome P450 liver enzymes (CYP enzymes) are induced, it would increase the rate of metabolism
increasing the rate of metabolism would ______ the action of the drug
decrease
If cytochrome P450 liver enzymes are inhibited, it would decrease the rate of metabolism (drugs stays in the body longer)
decreasing the rate of metabolism would _______ the action of the drug
increase
inhibition of cyp enzymes results in
less eyymes, less breakdown and drug stays in the body longer
induced CYP enzynes results in
increased enzymes which increases the breakdown which causes the drug to leave the body faster
what is conjugatioin
forming a compound by joining two or more chemical compounds
what is hydrolysis
reaction involving breaking of a bond in a molecule using water
describe phase II conjugation/hydroysis
hase II reactions hydrolyze or conjugate a drug to a larger polar molecule by adding other molecular groups such as glutathione, sulfate, and acetate
This reaction inactivates the drug or enhances the drug solubility and excretion rate into urine or bile
effect of Phase I and II reactions on a particular drug also are dependent on presence of other drugs taken by the patient at the same time
true
what are barbiturates
sedatives
inducers of enzymes mediating phase I reactions
taking barbituates are inducers so they will leave the body faster
true
other drugs that inhibit cause the drug to stay in the body longer
true
what drugs inhibit enzynes?
erythromycin
polypharmacology
taking several drugs together
3 outcomes of phase I and II of the liver reactions
Convert an active drug to inactive
most common outcome
inactive drug formed from the active parent drug
Convert an inactive drug form (prodrug) to active
inactive parent drug is converted to active drug after metabolism
Convert an active drug to active
an active parent drug is convrted to a second active drug
function of Phase I and II biotransformation is to
enhance the hydrophilic nature of a hydrophobic drug so that it can be excreted easily out of the body
what is excretion
movement of a drug and/or its metabolites out of the body
how is a drug excreted
Primarily through renal excretion (urine)
Also through biliary excretion (feces)
Minor amounts through respiratory (breath – i.e., alcohol, useful for Breathalyzer), and dermal routes (sweat)
Even smaller amounts through breast milk during lactation
25% of the entire blood in the body goes to the kidneys
true
why are kidneys are continually exposed to drugs in the blood stream
Renal flow comprises ~25% of total systemic blood flow
If a drug is still fat soluble when it reaches the kidney, it will be reabsorbed by the kidneys and placed back into the bloodstream
true
kidney function will affect drug excretion because
majority of drugs in the blood stream are filtered and excreted out by the kidneys
kidney function is affected, then excretion of the drug will take longer and can increase drug toxicity
true
increases toxicity and overdose
Kidney function is affected by many conditions including
Age (kidney function declines with age)
Drug toxicity
Altered kidney function from disease such as diabetes (impaired renal blood supply)
hypertension
renal diseases - polycystic kidneys & glomerulonephritis from any case
cancers
(diabetes, high blood pressure, tumors, cancer, polycystic, genetic conditions (alport, BOR) )
what is drug clearance
rate of elimination of a drug from the body relative to the concentration of the drug in the plasma
rate at which the drug would need too be cleared from the plasma to account for the change sought by the drug in the body
