Pharmacokinetics Flashcards
Pharmacokinetics (define): the study of how drugs are A. D. M. E. in the body.
Administered/absorbed
Distributed
Metabolized
Eliminated
Drug actions
what drug compounds do (at cellular and/or molecular level)
-Study of how drugs interact w/ CNS neurons and could change patterns of firing in neurons.
Drug effects
How drugs produce changes in body.
The ultimate endpoint of what those drugs are
Drug actions (examples)
how drug causes a K+ or Na+ channel to open
Drug actions vs. Drug effects
We known the drug effects, but don’t know what the drug’s actions are
Lithium example
- LiCl (salt) used to stabilize bipolar hi/lows.
- Not known particular receptor mechanism (changes at cellular membrane, neuron’s firing rate or changing pattern)
- Don’t know drug actions, but know drug effects.
- A
The two routes of drug ADMINISTRATION
Enteral
Parenteral
- A (i) Enteral
when a drug is administered into the GI system
Enteral drug administration examples
Oral (pills)
Suppository*
Under tongue*
- A (ii) Parenteral
when a drug is administered outside GI system
Parenteral drug administration examples
Intravenous
Sebaceous
Topical
Intramuscular
Unique factor to consider w/ enteral drug administration
B/c of human variability.
Body set up to contend w/ xenobiotics introduced in body.
Determining factor of how well drug is absorbed is:
it’s ability to pass thru sacks of salty water surrounded by a fatty membrane
Lipid solubility measured by using the
Partition coefficient
Drug has hard time passing through membrane without
Some amount of lipid solubility
The less _____ drug is, the more of it will be ______ in a lipid solution.
The more ______drug is, the more of it will be ______ in a polar solution.
charged, dissolved (x2)
Challenge for enteric (easy) route
pills must get through membranes (stomach, etc)
Partition coefficient (how derived)
- put drug in
- aggitate
- Take away 2 phases, measure how much of drug is in each (polar and nonpolar).
- that ratio is your partition coefficient
pKA definition
Is the pH at which drug is 50% ionized and 50% unionized
Drug pKa is a factor of drug absorption influence only w/
passive diffusion
For good drug absorption and distribution, you want drug to be more
non-polar
the pH of the _____ also determines the absorption, in part.
environment
pKa and drug administration (mnemonic):
Acid less ionized in acid
Base less ionized in base
A _____will be less ionized in an acidic environment (thus ____ absorbed better in acids)
A _____ will be less ionized in an alkaline environment (thus ____ absorbed better in bases)
Weak acid (x2) Weak base (x2)
Two main factors of drug absorption
- pH of environment
2. polarity (or nonpolarity) drug is
Amphoteric
Compound that can act both acid or base, depending on environment.
amphoteric drugs have two pKa’s depending on whether environment is A or B.
In more ___ environment (i.e.___) drug is more absorbed if it is a Weak Acid.
acidic, stomach
Stomach vs. intestines
Stomach more acidic, but intestines have bigger surface area.
Even if a WA drug can be better absorbed in the stomach, it still has greater potential to be absorbed in intestines because of the huge membrane surface area of intestines
____, or ____ soluble (unionized) molecules can pass thru cellular membrane via ____.
____, ionized molecules (____ soluble) need other ways to get across membrane (via a ________; a gatekeeper)
Very small, lipid, passive diffusion
Larger, water, membrane transporter proteins
Transmembrane processes (5 types)
- Passive diffusion
- Facilitated diffusion
- Active transport
- Passive transport
- (Phag/pino)cytosis
Transmembrane processes (difference between filtration and active transport)
filtration (facilitated diffusion) uses a transporter protein whereas active transport uses ATP and a transporter protein and goes across a concentration gradient.
Transmembrane process 2. Facilitated diffusion
(aka: filtration)
membrane protein creates an acidic tunnel for polar or larger molecules to pass through
transmembrane process 3. Active transport
requires transporter protein and needs ATP
Transmembrane process 4. Passive transport
requires transporter protein and concentration gradient
Transmembrane process 5. Phagocytosis and Pinocytosis
cell membrane necompases and pinches it in (if solid, phagocytosis and if liquid, pinocytosis).
Pharmacokinetic factor 2. Distribution
How much of a drug gets to the brain after absorption.
Key is in drug’s bioavailability
Bioavailability
Is the extent and rate a drug or metabolite enters the circulatory system and can thus access its site of drug action
Plasma concentrations in blood (IV vs IM vs ORAL)
IV: sharp peak of bioavailability and tapers off
IM: must be absorbed into bloodstream, thus lower peak than IV and tapers off
Oral: slower absorption and peaks relatively last.
5 main factors of 2. Drug distribution
- Drug absorption*
- Membrane proteins
- Metabolism
- Carriers
- Depot binding
Two primary membrane barriers important for pharmacokinetics:
a) Placental barrier
b) Blood brain barrier
a) Placental barrier
mechanisms are both physical and chemical (enzymes, for ex)
Baby gets mom’s blood supply and doesn’t have immune function.
Filters out stuff from mom that is bad for baby.
b) Blood Brain Barrier
Biggest hurdle for drug actions
Even if drug is in bloodstream, it still must pass thru BBB and needs a private pass to cross (unless it is nonpolar)
Brain capillaries contain tight junctions (not super leaky fenestra like in other capillaries) and astrocytes (in glial cells) foot processes that surround and protect.
Rule of thumb for tight junctions
<2000(Da) or smaller (must be tiny if polar) or lipid soluble with transporter.
Meningitis issue with BBB
Brain has shitty immune system, meningitis can pass thru BBB. So IV massive amounts of antibiotics hoping some pass through to get rid of infection.
Factor 3. of drug distribution
Metabolism (first pass)
First Pass metabolism via
Hepatic portal vein
First pass metabolism
liver will break down some of the drug (metabolize) first.
Must take liver metabolism into account with enteric drug administration (since all enteral blood vessels go to liver first via hepatic portal vein).
First pass occurs with/doesn’t occur with these administrations:
Not: IV skips first pass metab
Do: Anything enteral (oral, suppositories, etc).
Factor 4. of drug distribution:
Carrier proteins
- carrier proteins
For lipid soluble (nonpolar) drugs, since they have hard time in the polar (waterey) bloodstream.
Nonpolar brugs will leave bloodstream quickly without a carrier protein.
Carrier proteins are the answer of:
How to get lipid soluble (nonpolar) drugs around bloodstream
Carrier proteins are
Very watery
Very sticky
Large
Carrier proteins are only important for ____ drugs
Nonpolar
Most common carrier protein
Albumin
How does carrier protein work?
lipid sticks to carrier protein, rides bloodstream and pops off, immediately dissolves out of circulatory system and into local cells and tissues.
Without carrier proteins…
We would not be able to have nonpolar drugs distributed throughout body.
Carrier proteins extremely important for
Androgens (steroid hormones), which are nonpolar and need carrier proteins to get throughout body for their various functions.
It is good for drug to be fat soluble if it is administered ______, but not good if it is fat soluble with respect to it’s ______.
Enterally, distribution
Two considerations for nonpolar drugs WRT Depot Binding:
- How much will get to brain
2. How much will get stuck in fat
- Depot binding
When lipid soluble molecules leak out of capillaries, they’re fat soluble and will want to dissolve in fat (stored).
Depot binding only important for
nonpolar drugs
Depot binding example
THC is fat soluble circulated in bloodstream. More fat, more depot binding occurs.
Testing for THC if fat rapidly dissolves and THC released into bloodstream could create a false positive because deposits are released from fat if you lose lots of weight quickly.
Pharmacokinetics 3. Metabolism (of drug)
aka: Biotransformation
via metabolic enzymes, mostly in the liver but also present throughout the body
Metabolic enzymes
Mostly in liver
can either be membrane bound or soluble within cytosol. They’re not substrate specific and can biotransform a lot of different drugs
First pass metabolism (definition)
drugs absorbed within the GI tract have to first pass through liver before entering the heart and rest of the body via hepatic portal veinous system
First pass metabolism bypassing (ex)
Nitroglycerine can be completely broken down and eliminated in liver before rest of body when administered enterically. Must bypass 1st pass metabolism
Phase 1 reactions are
non-synthetic
Examples of phase 1 reactions
Oxidation
Reduction
Hydrolysis
Phase 2 reactions are
Synthetic: they conjugate drug with a new molecule
Phase 2 reactions examples:
Methylation
Acetylation
Amino acid conjugation
Most common phase reaction in metabolic enzymes are:
Oxidation reactions
The ____________ is to make the drug more polar, but not necessarily to deactivate them
Net effect of all metabolic enzymes
Metabolism of drugs in body is via
oxidation rxns
Misconception of metabolic enzymes purpose:
Doesn’t always inactivate drug/no longer acts for intended effect, instead is designed to make net effect of drugs more polar. Therefore, more water soluble and less able to enter cells and will stay in circulatory system longer until filtered out through kidneys.
Enzyme superfamily responsible for biotransformation of drugs
Cytochrome P450 (CYP) make drugs more water soluble/polar 66 different CYP enzymes in humans, but composition variance even if equal in weight and body type. Also present are sex differences wrt how drugs are metabolized.
Two interesting properties of CYP enzymes
- Induction
2. Pharmacokinetic tolerance
Induction
is an increase in CYP enzyme activity following prior exposure to a drug or toxin. More enzymes produced to breakdown with more exposure (liver will adapt). This results in less effect of a drug
Pharmacokinetic tolerance
occurs when more drug is needed subsequently to provide the same drug effect because of induction of its CYP metabolic enzyme(s). The more chronic use results in induction and results in less effect of a drug because liver becomes more effective at breaking down that drug.
Bioactivation (definition, names of the steps and example)
occurs when drug taken is not in active form, but only becomes active after metabolism by enzymes.
Ex:
- willow bark (pro drug… not active)
- Bioactivation (drug… active form) turns it to Aspirin
Pro drug is not ready to
Act on receptors until metabolized in liver
Cross-induction
occurs when more drug is needed subsequently to provide the same drug effect because a different drug induced its metabolic enzyme(s). Important when talking about drug interactions.
Enzyme inhibition (definition and example)
Can occur when a drug or toxin reduces the metabolic activity of certain enzymes.
Flavanoids (grapefruit juice) blocks certain CYP enzymes and therefore enzymes no longer active to metabolize other drugs, resulting in drug buildup in bloodstream.
Danger of cross-induction
If you take drug A regularly and another drug B may not have much effect because drug A already induces liver’s CYP enzymes and thus are more active, breaking down drug B more than expected. Increase drug B to get the same effect. If you stop taking drug A, liver enzyme CYP could go back down and stop metabolizing higher levels of drug B. This results in toxic/higher levels of that drug in your system.
Cross-induction is a type of
Drug interaction
Pharmacokinetics 4. Elimination (of drug) occurs in:
Mostly kidneys Other sites (bile, lungs, sweat, milk and feces)
T(1/2)
The time takes for a drug to fall to half peak level
Integration of A.D.M.E.
Must look at all ____ to see how much of drug will stay in _______ and for how long is the main way that it is calculated is the ______
A.D.M.E., circulatory system, half-life
Caveats of half-life
Liver keeps breaking down drug with every pass.
Other enzymes in body (but mostly in liver)
Overall, A.D.M.E. effects collectively dictate…
How much drug gets into brain and how long it is going to stay there.
Route of administration
is what determines the peak of amount of drug circulating and half-life.
