Pharmokinetics Flashcards
Pharmacokinetics
what the body does to a drug
absorption, distribution, metabolism, elimination(ADME)
molecular weight
smaller drugs cross membranes more easily
most drugs are <400-500 Da
drugs binding to protein effects size
plasma protein binding
drug enters circ and binds to protein
drug+protein=too big
protein bound drugs remain in plasma until they are no longer protein bound
solubility
lipid (lipophilicity) vs water (hydrophilicity)
lipophilic drugs more easily diffuse through membranes
hydrophilic confined to plasma, ECF
ionization
unionized (nonpolar, lipophilic) drugs distrubute more widely
dependent on pH, pKa
weak acids become unionized in acidic environments
weak bases become unionized in basic environments
concentration gradient
higher concentration (can alter w dose and route)= more drugs for diffusion
assumes there is enough blood flow to area of drug aministration
passive diffusion
no external energy required
at equilibrium, net transfer is 0
non selective
non saturtable (1st order linear kinetics)
rate of diffusion proportional to concentration gradient**
Carrier mediated transport
drugs lacking sufficient solubility for passive diffusion
carrier may be specific to drug
competition for carrier
transport for this mechanism can be saturated
these drugs typically mimic an endogenous substance
carrier mediated facilitated diffusion
special transport proteins in the plasma membrane
goes with concentration gradient
does not require energy
active transport
carrier mediated
goes against concentration gradient
can be saturated
requires energy
intravenous
drug injected into bloodstream- skips absoptive phase (100% absorption)
advantages: highest concentrations and potentially highest efficacy
disadvantages: highest risk of toxicity, technically difficult, risk of intracarotid injection (goes directly to brain= bad)
prefered in ER (ensures drug is delivered)
intramuscular
muscles are highly vascular, absorption is often high
advantages: easy to perform (large animals easier than smaller)
disadvantages: possibility of admin in vessel, painful, may cause muscle necrosis, abcess, infection
often 2nd choice in ER if you cant hit a vein
Subcutaneous
moderate to high absorption (more variable than IM)
advantages: easy to perform, less painful than IM
disadvantages: during dehydration and/or shock the skin receives less blood flow
are lipid soluable drugs absorbed faster or slower than aqueous?
slower than aqueous
enteral vs parenteral
enteral: admin per GI tract (ex. oral, rectal)
parenteral: everything else (IV/IM/SQ)
oral administration (PO)
absorption ranges from 0-100% (most variable)
slowest
many species differences
effected by feeding/diet
not prefered in ER
advantages: cheap, can be easy
disadvantages: drug loss (during admin, vomit, degredation by stomach acid, rumen), affect on GI flora
reasons for poor oral bioavailability
- Drug not delivered from its formulation to absorption site in GIT
–Needs to be Water soluble enough to go into solution but Lipid soluble enough to be absorbed across the GI membrane
–Drug must go into solution before it can be absorbed! (May be a rate limiting step for lipid soluble drugs)
–Drug formulations may have solubility enhancers to improve absorption (Compounding??? solubility is questionable) - drug is decomposed in GIT
- drug is complexed in GIT (bind to other things)
- drugs need a carrier mediated transport and dont have one
- ion trapping (ionized drugs trapped inside cell walls, NSAIDS in stomach- ulcers)
- some drugs metabolized in gut or liver (first pass metabolism)
first pass metabolism
- A large percentage of drug absorbed is immediately metabolized in the gut or liver prior to absorption into the systemic circulation
- Drugs with high first-pass metabolism are often not suitable for PO administration
- Do not reach adequate plasma concentrations
ways to avoid first pass metabolism
alter route of administration
* alter route of adminstration (transmucosal, per rectum, transdermal)
* not all drugs are suitable for enteral admin
* suitable drugs are lipid soluable, hightly potent (lots of drug is lost), and unionized at mucosal pH
oral transmucosal
Aka buccal or sublingual
Membranes are relatively permeable
Rich blood flow
Rapid uptake of a drug into systemic circulation to avoid first pass metabolism
non oral transmucosal routes
Inhalation, nasal, ocular, vaginal, rectal
per rectal
advantages: access when unconsious or vomiting, no taste, can recover drugs before absorption is complete, can bypass first pass metabolism
disadvantages: limited surface area, lower fluid content, microbes, too far cranial drains into portal vein (first pass metabolism), drug may not stay where you put it
transdermal
drug absorbed through skin into circ
not the same as topical (stays on top of the skin)
few drugs work this way
Cmax
maximum plasma concentration
* units: mass/volume (ug/ml, ng/ml)
* typically highest for IV, lower for PO/IM/SQ
* Cmax often determines the magnitude of effect and adverse effects
Tmax
time to maximun plasma concentration
* units: hour or min
* for IV dosing 2-3 min, variable for PO/IM/SQ
* Tmax often tells you when the effect/adverse effect will occur; used for drug monitoring
area under curve (AUC)
Influenced by Cmax, Tmax
Indicates how much drug is absorbed
units: concentration/time (ug/ml hr)
bioavailability (F%)
Percentage of administered drug that appears in the bloodstream
after dosing
Two types – absolute and relative
A- bigger AUC
closer to IV drug
Absolute bioavailability
Absolute bioavailability compares EV drug to IV drug
Calculations
F=AUCev/AUCiv * 100 (dont memorize)
relative bioavailability
Compares EV (extravascular) drug to EV drug
May be routes of administration
May be different formulation
Calculations
F=AUCev/AUCev * 100 (dont memorize)
A- IM
A- solution
bioequivalence
Basically says two drugs will have the same effect
FDA proprietary = generic formulations
Generic = generic
FDA approved/generic vs compounded??? (not always bioequivalent)
AUCs and Cmaxs should be within 20% of each other
FDA and generic
GI disease effecting absorption
enteral absorption affected
* diarrhea, vomiting, proliferative diseases (of small intestine)
liver disease affecting absorption
Liver disease can decrease first pass metabolism and therefore increase oral absorption of some drugs that normally undergo high first pass effects.
dehydration affecting absorption
first affects SQ route
Dehydration, unless very severe, will most affect drugs administered via the SC route, resulting in decreased drug absorption
drug distribution
Reversible transfer of drug between the blood and the extravascular fluids and tissues of the body
path of drug distribution
From plasma, drug 1st distributes into the interstitial fluid
AKA extracellular fluid
Between and outside the cell
Next, the drug may cross biological membranes to enter into intracellular fluid, protected tissues
solubility affecting distribution
Nonionized lipid soluble drugs- Easily cross membranes and distribute widely
Ionized water soluble drugs -Can’t easily cross membranes and most remain in the plasma and ISF
molecular weight affecting distribution
Low molecular weight
* Cross membranes easily
High Molecular weight
* Includes monoclonal antibodies
* Includes protein bound drugs
* Can’t cross membranes and remain in the plasma
pH and pKa affect on distribution
Blood is very slightly alkaline…and always should be!
Average 7.35-7.45
Acidic low pKa drugs will be mainly ionized- Limited ability to cross membranes
Basic low pKa drugs will be mainly nonionized- Cross membranes more readily
blood flow affecting distribution
Initially distribute to high blood flow, low volume organs- Brain (lipophilic), liver, kidneys
Next – lower blood flow, high volume organs- Muscle
Finally – low blood flow organs- Fat (lipophilic, can store drugs in fat depot then slowly release- essentially inactivating drug), skin (SQ most affected by dehydration!)
protein binding affect on distribution
Only a fraction of drug in circulation will be bound Which means a fraction of drug is free in circulation
ONLY FREE DRUG IS ACTIVE!!!
ONLY FREE DRUG CAN CROSS MEMBRANES
Bound drugs act as a reservoir- Only free drug gets metabolized and eliminated
As free drug concentration decreases, bound drug becomes free to maintain equilibrium (constant free drug fraction; liver)
blood brain barrier affect on distribution
Can’t go between cells….have to go through cells
-Tight junctions between cells
-Basal membrane
-Pericytes
-Layer of astrocyte foot processes
Go through cells via:
-Lipid soluble, nonionized, unbound OR
-Carrier-mediated; active transport
P-glycoprotein efflux pumps
Carrier mediated active transport
Pump drugs OUT
present at protected sites (blood brain barrier, eye, prostate, placenta, alveoli)
MDR1 mutations are the lack of these pumps (accumulation of drugs, toxicity)
inflammation effect on drug distribution
Increased drug permeation
Increased protein
Drug concentrations decrease as inflammation decreases
Lipid soluble, nonionized, unbound drugs best
Volume of distribution (Vd)
Theoretical volume of fluid into which a drug appears to distribute
Vd=dose/max plasma concentration
Measure of how far beyond the plasma a drug distributes (Plasma, ISF, intracellular, protected sites)
Need to choose a drug that will get to the site of action- does NOT tell us if it gets to a specific tissue
Higher doses that result in lower plasma concentrations will seem to have a larger Vd
ex: if a dose is admin to the ocean concentration will be low
if a dose is admin to a cup of water, concentration will be high
ex: small Vd infers the drug stays in the plasma
medium Vd infers drug will stay in plasma and interstitial fluid (treat diseases in plasma and ISF)
large Vd infers drug distributes to plasma, ISF, intracellular fluid, potentially protected sites
what is Vd calculated from?
must be calculated from IV dose
need bioavailability must be 100%
Drug A compared to Drug B
Assuming an equal PPB, which is more lipophilic?
B- can cross more membranes
Drug B compared to Drug C
Assuming equal lipophilicity, which drug is more protein bound?
B
Drug A compared to Drug C
Assuming equal lipophilicity and protein binding, which one has a smaller MW?
C
age affect on distribution
Neonates have more body water
-More water = larger Vd = lower plasma concentrations of water soluble drugs
Old people are shriveled and dry
-Less water = smaller Vd = higher plasma concentrations of water soluble drugs
Ex: Puppies
weight effect on distribution
Neonates have very little fat
-Less fat = smaller Vd = higher plasma concentrations of fat soluble drugs
Obese animals have lots of fat
-More fat = larger Vd = lower plasma concentrations of fat soluble drugs
dehydration effect on distribution
Less fluid
Higher plasma concentrations of water soluble drugs
diseases causing fluid accumulation affect on distribution
Cardiac disease, Renal disease, etc.
* Water soluble drugs will distribute to that fluid
-Lower plasma concentrations, larger Vd
-May need to increase dose
* Lipid soluble drugs will not distribute into that fluid
-Higher Cp, smaller Vd
-May need to dose on lean body mass
-weight of animal – weight of fluid
prodrugs
converted from inactive to active form during metabolism
what is the main organ or metabolism?
liver
phase 1 reactions
oxidation, reduction, hydrolysis
make drugs more polar
performed by CYP450 enzymes
phase 2 reactions
conjugation (glucuronidation, acylation, methylation, sulfation)
uses UDP-glucuronosyltransferases
species specific differences
CYP450
non selective enzymes
major source of variability in drug metabolism (within and between species)
mostly in liver but can be in GIT, skin, kidney
can be induced and inhibited by drugs
CYP450 inhibitors
cause body to produce less CYP450
Overall effect is to increase concentrations of other drugs that are substrates of P-gp and CYP450 (inhibit metabolism= increased concentration)
CYP450 inducers
cause body to create more CYP450
Overall effect is to decrease concentrations of other drugs that are substrates of CYP450 (increase metabolism of those drugs)
What is the consequence of being an ultra-fast metabolizer?
What is the consequence of being a slow metabolizer?
How does this change with a drug that has an active metabolite?
* What if the metabolite is more toxic than the parent drug?
What is the consequence of being an ultra-fast metabolizer?
-less efficacy
What is the consequence of being a slow metabolizer?
-higher toxicity
How does this change with a drug that has an active metabolite?
* What if the metabolite is more toxic than the parent drug?
-ultrarapid metabolizer: more toxic, slow metabolizer: less toxic
factors affecting metabolism
age: decreased in young and very old
gender
disease (hepatic)
genetics
species!!!!! (and breed)
enzyme saturation (zero order kinetics)
drug clearance
- Definition: Volume of blood cleared by a substance per unit time
- Reported in mL/kg/min (or volume/weight/time)
reflects rate of drug elimination from body (elimination and metabolism)
encompasses all organs capable of elim drugs
Total body Cl = Clhepatic + Clrenal + Clother
hepatic clearance
Hepatic clearance is dependent on the blood flow to the liver and the intrinsic metabolizing capacity for the drug
(Hepatic blood flow) x (amount of drug extracted by liver)
perfusion (flow) limited drugs
- High hepatic extraction ratio drugs
- High concentration of metabolizing enzymes in the liver
- Liver can metabolize as fast as the blood can deliver- Free drug only, PPB (protein binding) can be rate limiting
- Linear or first-order kinetics
capacity limited drugs
- Low extraction ratio drugs
- Liver has low capacity for metabolism due to low concentrations of metabolizing enzymes
- Blood delivers faster than the liver can metabolize
- PPB protein binding does not limit, as free drug concentrations exceed metabolizing capacity
- Zero-order or nonlinear kinetics
drug excretion
- Irreversible elimination of drug from the body: Unchanged (parent drug) or Metabolites
Major routes: kidneys (urine), bile (GIT, feces)
minor routes: milk, lungs, saliva, sweat
glomerular filtration
filtration, passive
small protein unbound molecules
much is reabsorbed
tubular secretion
in prox tubule
active (ATP), carrier mediated
saturable (can be competition for carrier)
tubular reabsorption
in distal tubule
usually lipid soluable drugs, unionized at urine pH
ion trapping
-acidic drugs are unionized in acidic pH urine- can move back to blood passively (reabsorbed)
-basic drugs are ionized in urine and stay in urine more
species differences in tubular reabsorbtion
herbivores have alkaline urine (basic drugs more likely to be reabsorbed, very difficult to make urine acidic)
renal disease affect on renal elimination
higher plasma drug concentration and prolonged drug effects (less excretion)
biliary elimination
secretory process
fairly non specific
polar, large MW compounds
free drug only (not protein bound)
biliary elimination in MDR1 dogs
MDR1 dogs have decreased biliary clearance of drugs eliminted into bile
increased drug concentration and potential toxicity
enterohepatic recirculation
drug is absorbed and enters liver
- some of drug is conjugated, extreted into gallbladder
- drug excreted into small intestine and unconjugated when gallbladder contracts
- drug is reabsorbed and enters liver again, unconjugated and reaches plasma
- In overdose situation, administration of binding agents (activated charcoal) may still be effective even hours after drug intake
- remeber: not all species have gallbladder (horse, rat) but may still have secondary absorption peak from other factors (formulation factors, colon absorption, urine reabsorption)
half life
Time it takes for plasma concentrations of a drug to decrease by 50%
It is NOT the time it takes for 50% of the dose to be excreted from the body
Why may a drug be effective despite low plasma concentrations?
Dosing interval will be longer than half life
Antibiotics with prolonged PAE- post anitbiotic effect (aminoglycosides)
Drugs that accumulate in cells/tissues (e.g., omeprazole)
Drugs whose metabolites are active and have long T½ (diazepam)
Drugs whose effects are irreversible (aspirin)
Why may a dosing interval be shorter than the half life?
drugs with long half lives
gives longer therapeutic concentrations
less fluctuation, more accumulation
drug accumulation
When drug is administered before previous dose is completely eliminated
Degree of accumulation depends on:
* How muchdrugis being added to the body
* How much is being eliminated from the body during DI
Can be controlled by changing the dosing frequency
steady state concentration
The amount of drug in the body will continue to accumulate until steady state concentrations in the plasma are reached
Intake of a drug is equal to its elimination
Cmax and Cmin are basically the same from dose to dose
Assumes stable dosing interval
Occur after 5 half-lives
Point of maximum effect
Point at which adverse drug reactions occur
Dose-dependent
assumes first order linear kinetics
Linear first order kinetics
*** Elimination of a constant drug fraction (%) per unit of time **
* Proportional to the drug concentration
* T1/2 does not change with dose
“Dose-independent” PK: does does not effect elimination
Most therapeutic drugs are first-order within clinical dose ranges
linear increase in Cmax as dose increases
how many half lives until a drug is 99.9% eliminated in first order kinetics?
10
nonlinear, zero order kinetics
**Elimination of a constant drug amount per unit of time **
Not proportional to the drug concentration
T1/2 does change with dose
“Dose-dependent” PK
Most therapeutic drugs will be zero-order at very high doses
*Overdoses – makes treating them even harder
Almost any drug will exhibit zero-order kinetics at high enough doses
Disproportionate increase in plasma concentrations compared to dose
main reasons for non linear kinetics
Mainly: Saturation of metabolizing enzymes in the liver: Capacity-limited; low ER drugs
Others:
* Saturation of GI metabolizing enzymes
* Saturation of carrier-mediated absorption
* Saturation of tubular secretion
* Inhibition or induction of hepatic metabolizing enzymes (Drug-drug interactions, Auto-induction/inhibition)
loading doses
For drugs with long half-lives that require too long to reach therapeutic concentrations
1st dose higher than subsequent
constant rate infusions
For drug that have a VERY short half-life
For drugs with a narrow TI that require drug concentrations to be maintained within a very narrow range
what influnces half life?
Volume of Distribution and Clearance
T1/2 = 0.693*Vd
Cl
