Lectures 4&5 - Pharmacokinetics Flashcards
what is the main point of pharmacokinetics?
trying to predict how much drug gets to the site of action
what are the four main points of study in pharmacokinetics?
- absorption
- distribution
- metabolism
- elimination
“ADME”
what happens after you administer a drug?
1) the drug needs to be absorbed from its site of administration
2) it needs to travel in the body to reach its target tissues
3) over time, the effects of the drug “wear off” because the drug is eliminated
understanding what controls _____ and ______ is extremely important in order to maximize the amount of time that the drug is present in an ______
absorption, elimination, optimal concentration
the minimum plasma concentration of a drug needed to achieve sufficient drug concentration at the receptors to produce the desired pharmacologic response
minimum effective concentration (MEC)
on a graph, the space between the MEC(desired) and the MEC(adverse) is known as the:
therapeutic window
what are the five main factors that can affect steady state concentration and fluctuations:
- dose
- time between doses
- bioavailability
- clearance
- half-time
what are six important considerations when thinking about the route of drug administration?
1) convenience (oral is very easy)
2) bioavailability
3) processing (hepatic portal circulation and first-pass metabolism)
4) physical properties of the drug
5) chemical properties of the drug
6) site of desired action
what is the difference between enteral drugs and paraenteral drugs?
enteral drugs must pass through the digestive system in some way, and paraenteral drugs are administered in a way that is not through the mouth or anus
what are the three main routes of enteral drug administration?
1) oral
2) sublingual
3) rectal
the most common route of administration for prescription drugs
oral administration
what is the rate of absorption for oral drugs?
slow and may be affected by intake of food (30-90 minutes)
route of drug administration with rapid absorption and delivery (3-5 minutes) and bypasses the “first pass metabolism” effects
sublingual administration
route of drug administration where the drug is delivered directly into the systemic circulation, so very rapid onset (seconds to minutes) of action
intravenous (IV)
route of drug administration where the drug is injected into the muscle, or just below the skin; rate of absorption depends on blood flow to the site (10-20 minutes)
intramuscular/subcutaneous
route of drug administration where the drug is absorbed through the epithelium in the lungs, and can be very rapid (2-3 minutes)
inhalation
a convenient route of drug administration with slow and sustained absorption (minutes to hours)
topical/transdermal (ointment or patch)
what are the eight major factors affecting drug absorption from the gut?
- particle size and formulation
- ionization and lipid solubility (pH)
- GI motility
- sphlanchnic blood flow
- microbiota
- gut metabolizing enzymes
- drug transporters
- physiochemical factors (ie: Ca++ or Mg++)
what are the four major mechanisms of solute/drug transport across GI membranes?
- passive diffusion
- facilitated transport
- active transport
- paracellular transport
direction of transport is determined by the solute concentration gradient or electrochemical gradient without an energy input
facilitated transport
drugs can be transported against a concentration gradient with the consumption of ATP
active transport
requires molecular mass less than 250Da, and molecules with a longer, linear structure. these pores can also have different charge-selectivity
paracellular transport
what is first pass metabolism?
if ingested orally, drugs absorbed in the gut then pass through the hepatic circulation before entering the systemic circulation. this is a major site of metabolism that strongly influences the bioavailability of many drugs
what are the two key mechanisms leading to elimination?
1) enzymatic metabolism (biotransformation) - occurs mostly in the liver
2) excretion
in general, emzymatic metabolism involves _____ and _____ processes
phase 1, phase 2
what is phase 1 enzymatic metabolism?
the Mixed Function Oxidase system generates oxidative modifications of drugs (usually makes the molecule more aqueous)
true or false: phase 1 metabolism always inactivates a drug
false. it may also lead to enhanced pharmacological activity, different activity, or make the compound more toxic
what is the major enzyme class involved in phase 1 emzymatic metabolism?
cytochrome P450 enzymes (CYPs)
what is phase 2 enzymatic metabolism?
conjugation of the parent compound, or phase 1 product, with large polar adducts to make the product more prone to excretion (essentially adding a large functional group to the molecule)
genetic variation in CYP enzymes leads to:
individual differences in how we respond to drugs
the most widely expressed CYP in the liver and metabolizes ~75% of therapeutic drugs
CYP3A4
sometimes toxic/reactive intermediates are formed in first pass metabolism, which leads to:
hepatotoxicity
the fraction of unprocessed/unaltered drug that reaches the systemic circulation after administration by a particular route
bioavailability (F)
bioavailability predominantly reflects pre-systemic clearance in the:
GI and liver
what is oral bioavailability?
a product of fraction absorbed (Fa), fraction escaping gut-wall elimination (Fg), and fraction escaping hepatic elimination (Fh)
what is the formula for oral bioavailability?
F = (Fa)(Fg)(Fh)
bioavailability is calculated based on:
the blood concentration-time profile obtained through in vivo testing
bioavailability depends on:
the drug and its susceptibility to enzymatic breakdown
how do you calculate bioavailability using a blood concentration-time profile?
F = (area under the curve of the profile in oral administration) / (area under the curve in intravenous administration)
list the three critical factors governing drug distribution
1) concentration gradient of free drug between the blood and target organ/compartment
2) solubility of drug in the target organ/compartment (relative water/fat solubility)
3) blood flow of the target
what fraction of the drug can be considered pharmacologically active?
usually only the free fraction
a drug in blood exists in two forms:
bound and unbound
if protein binding with a drug is reversible, then:
a chemical equilibrium will exist between the bound and unbound states
extensive plasma protein binding will _____ the amount of drug that has to be absorbed before _____ of unbound drug are reached
increase, effective therapeutic levels
drugs distribute from the blood into three main compartments:
- viscera
- muscle
- fat
highly perfused organs which receive rapid drug distribution
viscera
well perfused tissues with large mass, and quick distribution of drugs despite their low lipid content
muscle
tissues with a poor blood supply and have a slow distribution of drugs
fat
drugs with high lipid solubility will accumuulate in:
fat
provides a relative comparison of how well different drugs are distributed into tissues
apparent volume of distribution (Vd)
what is the formula for the apparent volume of distribution?
Vd = (total amount of drug in the body) / [drug]
true or false: volume of distribution is a concept, and does not represent a real volume
true
volume of distribution is a major determinant of:
half-life and dosing frquency of a drug
if the drug is evenly distributed throughout the body the calculated Vd will be equal to:
the total body water value
if a drug has a Vd of <3L, the drug is mostly in the:
plasma
if a drug has a Vd of ~17L, the drug is mostly in the:
extracellular water (will not cross biological membranes)
if a drug has a Vd of ~40L, the drug is:
evenly distributed throughout the body
if a drug has a Vd of >40L, then:
tissue binding exceeds plasma protein binding
if a drug binds extensively to plasma proteins, it will have a:
low Vd
if a drug is unable to cross membranes, Vd cannot be larger than:
the extracellular space
overall drug concentration is typically described by a:
half life (t1/2) or elimination rate constant (k)
an exponential decay equation can be used to describe elimination in:
first-order kinetics
when drug concentrations are much higher than the affinity of a key enzyme involved in their elimination
capacity-limited elimination (zero-order kinetics)
what is single compartment distribution?
a type of distribution where the drug is contained within a single compartment
in single compertment distribution, if an elimination pathway is present, the drug concentration decreases with:
exponential decay kinetics
the rate of elimination depends on the:
concentration of the drug
what is multiple compartment distribution?
after administration, the drug distributes into multiple compartments
in multiple compartment distribution, if an elimination pathway is present, the drug concentration in the blood determines the rate of elimination, but:
the reservoir of drug in the tissues can prolong the lifetime of the drug in the body
true or false: in a one compartment model, the elimination rate (k) of the drug is dependent on the route of administration
false, the elimination rate is independent of the route of administration, and will be the same regardless
in a two compartment model, the rate at which the drug is eliminated depends on:
the rate that it takes to get back into the blood from its peripheral compartment
what are the two primary routes of drug excretion?
1) bile/feces
2) urine
