pharmacokinetics Flashcards
parmacokinetics = ADME
ADME Absorption Distribution Metabolism Excretion
ratio of molar mass to the molar mass constant
molecular weight MW
Molecular weight – why important for drugs
g/mol
most drugs in range of 250-450
* passage through pores
solubility goes up as _____ goes up
temperature – usually
the maximum concentration of a substance that may be completely dissolved in a given solvent at a given temp/ pressure
solubility
the only form of an aqueous solution that a drug can be absorved into the gen circulation to exert a therapeutic effect
aqueous solubility
factors that affect drug solubility 4
- temp
- multiple solutes
- solute/solvent polarities
- pH
drug must be soluble in _______ to pass through membrane and soluble in ____ to be disolved. conundrum
lipid-
water
solvents may be ______, _______, or _______
polar, semi-polar, non-polar
like dissolves _____
like
semi-polar solvent ex.
alcohols and ketones–may be added to improve solubility of polar and non-polar liquids
molecular state=
ionic state=
undissociated states -
dissociated states
altering the pH of solution or using the ____ form of the compound may ^ or v solubility
salt–
Form a solvent system of optimum polarity or mix solvents of dif polarities to form a solvent system of optimum polarity to dissolve the solute
solvent blending or cosolvency
most drugs exist as weak _________; either weak ______ or weak _______
electrolyte-
acid or base
molecule that takes on (-) by giving H+
acid– HA = A- + H+
molecule that accept proton and become + charge molecule
cation- anion
BH+ = B + H+
salt form
A- or BH+
the pH at which 50% of the molecules are ionized and 50% are unionized
pKa
pKa
pH at which 50% of the molecuels are ionized and 50% are unionized
if has + or - sign
soluble in water
unionized form of acid or base (respectively)
HA or B
more soluble salt form:
biologically active acid or base:
A- or BH+
HA or B
In biological systems drug will move back and forth
henderson-Hasselbalch equation
pH = pKa + log study pic on page 6 of notes
in acidic environment if pH < pKa
more HA and BH+
in basic environment if pH >pKa
more A- and B
a weakly acidic drug will accumulate on the more ____ side of membrane
basic
weakly basic drug will accumulate on the more _____ side
acidic
for our purposes HA=
nonpolar so well move through GI wall –HA will be made in highly H+ environment of stomach–trapped out of stomach
in stomach HA will be made preferentially from A- + H+ then
move out of stomach and be turned back to A- + H+ and be trapped in blood
interplay of ionized and unionized form leads to
trapping–as in kidneys–> body can alkalized urine to “trap” drugs wo we can get rid of them
some drugs are weak base liquids naturally but can be _____ with another ____ to make it a _____
pairing-
ion-
salt
second name in generic drug name
salt molecule that drug is paired to– i.e. fluiticasone PROPRIONATE
pairing can be through ____ or _____ bonds
covalent or ionic
zonula occludens aka
tight junctions (protected tissues)–limit membrane permeability to ion channels
protected tissues
BBB
movement into area through GAP between cells
paracellular pathway–some leaky for small solutes and ions
paracellular pathway vs.
transcellular pathway (BBB’s only path)
no energy needed aside from concentration gradient
passive diffusion
key method for drug distribution to unrestricted tisues
paracellular pathways
key driving force for paracellular pathway
hydrostatic pressure (also influenced by oncotic pressure and drug concentration gradient)
requires energy
active transport
Rate of diffusion=
concentration grade X surface area X diffusion coefficent/ Membrane thickness
diffusion coefficent =
permeability/ molecular weight
Diffusion rate increased by:
- ^ concentration gradient (large dif inside and out)
- ^ surface area
- ^ diffusion coefficent (^ perm membrane & v MW)
- small membrane thickness
- ^ lipid/water partition coefficient (lipophilic solutes have larger coefficients)
Active transport is: 2
- Primary active transport (protein directly uses energy 2 transport
- Secondary active transport uses electrochemical potential difference to fuel transport (coupled transport = symporters/antiporters)
process of engulfing particles or dissolved materials by cell
- endocytosis
2. exocytosis
connected to absorption is the _____ __ _______
route of administration–formulated w/ this in mind
why would DISSOLUTION/ ABSORPTION rate need to be changed?
to prolong the duration of action (“controlled release” “extended release”)
step 2 of drug absorption
dissolution–usually takes place in stomach but can be coated for later release
How is dissolution rate slowed
- water-insoluble coating
- drug embedded in matrix
- etc.
Mostly absorbed in L intestines
if absorption slowed too much
active drug will be excreted
drug in
Stomach:
Small intestines
Large intestines
2-4 hrs (depends on acidity–more food=^acidity–> ^ dissolu.)
4-10 hrs
12-15 hrs
oral drug must cross _____ ____ lining GI tract before entering circ system
epithelial cells
time drug given
zero time
the extent and rate at which the active moity (drug or metabolite) enters systemic sirculation
bioavailability
bioavailability of IV drug admin
100%
moity
drug or metabolite
causes for low bioavailability
- insufficient absorption (insufficient time, reduced absorption)
- first-pass metabolism
- age, sex, physical activity, genetics, stress, GI problems, surg, etc.
Bioavailability assessed by AUC
area under the curve–
X axis: time
Y axis: plasma drug concentration
AUC of IV admin at zero time
100%
biovailability (AUC) measured with
frequent drug draws after drug administration
time when maximum plasma drug concentration occurs
peak time (most widely used general index of absorption rate)
Tmax
time it took to reach Cmax (peak drug concentration in plasma)
process of the delivery of a drug from systemic circulation to tissues
distribution
distribution to –>
extravascular fluid vs.
site of action
ECF and ICF in __________ equilibrium
osmotic–solute concentration on each side are balanced) i.e. no osmosis
fluid component of blood
plasma (intravascular compartment) of ECF
kidney has speciealized cells that detect the ________ ______ gradients–> signal to either ^orv pressure
hydrostatic pressure
cond. too much fluid in interstitial compartment
edema
interstitial compartment supplied and collected by
lymph vessels
space where there is no physiological functions for that fluid
“third space”
TBW raises as we get ______
older
Two phases of distribution
- cardiac output and regional blood flow
2. total equilibrium of blood
Vd –pg 28 in packet
apparent volume of distribution–refers to the space in the body into which the drug apears to disseminate
Vd
over time: plasma => plasma+interstial fluid=>plasma+interstitial fluid+intracellular
just in plasma:
low Vd- (mostly likely bound to plasma proteins cant escape)
large concentration
distributed to all compartments
high Vd-
small concentration
Vd tells us _____ drug is distributed but not ______
where-
why
proteins in general are weakly ____
basic – likes to bind to acids–so acidic drugs will bind to albumin and stay in blood plasma
basic drugs tend to want to bind to ____ ______
tissue proteins (vs. plasma)–thus high Vd
most common protein in whole body
albumin in plasma–made in liver
drug able to have physiological effect
unbound and ionized–non-depot bound
alpha1- acid glycoprotein and lipoprotiens
binds weak bases in plasma–low CAPACITY high AFFINITY
lipoprotein types
May bind drugs when albumin saturated
low density lipoproteins LDL
very low density lipoproteins VLDL
High density lipoproteins HDL
lipoproteins bind
basic drugs
drugs can also bind too _______
erythrocytes–45% of plasma volume–
*protein binding is considered when drugs designed, thus problems arise when _____ blood proteins produced
less–
less albumin w/ liver disease, protein catabolism, protein distribution, ^ renal excretion
adjustments in dosing based on protein binding must be made considering:
- pt health (renal disease hypoalbuminemia, liver disease, age, sex, edema, BMI, relative blood flow, capillary permeability
sexual dimorphism in relation to drug dosing
physiological and hormonal
age differences in relation to drug dosing
aging affects every organ–^ toxicity due to v excretion
BMI range in drug studies important due to
lipophilic drugs can alter drug concentration/distribution-
may see: “dose using ideal body weigt” –same for fat/thin ppl
“dose using adjusted body weight” on label means
estimate the proportion of adipose tissue that distributes medication
“dose using total body weight” on label means
more drug given to obese pt
imp for drug dosing in relation to circulatory system
- relative blood flow
- cardiac output
- specific tissue perfusion rates
distribution slow in
poorly perfused tissues (muscle, fat)
^ perfusion rate
^ drug concentration
the rate of blood flow through capillaries per unit mass of tissue
perfusion rate (depends on amount of blood flow & size of tissue)
capillary permeability
drug gets out mainly using pericellular pathway: greater->less permiable
liver>kidney>muscle = fetus > Brain
lipid solubility most important when trying to get drugs to _____ ______
restricted spaces
ion trapping
wealy acidic drugs are _______ in _____ ________
trapped in basic environments
wealy basic drugs are trapped in _______ ______
acidic environments
water soluble drugs (dissolve in water) tend to stay in
blood and the interstitial space (DRUG RESERVOIR)
tetracyclin loves
calcium–accumulates in teeth (yellow)
resevoir for lipid soluble drugs
adipose tissue
tissue reservoir ex.s
Bone
GI tract
Thyroid
Astrocyte foot processes secrete _____ to promote tight junction formation
paracrines
epithelial cells of the _____ ____ also contain ____ ______–contributing to BBB along w/ astrocytes
choroid plexus
tight junctions
inflamation can break down barrier
acid in acidic environment will be in _____ form
bound–HA
because much free H+
- placental barrier somewhat like ____
- fetal plasma is slightly more _____ than mothers, thus ion trapping of ____ drugs
- BBB
- acidic, basic
the irreversible removal of drug from the body by all routes
drug clearance
____ and _____ clearance mechanisms
simple and complicated
MAJOR organs for drug clearance
liver & kidney
liver cells
hepatocytes
minor drug clearance systems
- sweat glands
- lungs
- GI tract
- breast milk
two drug clearance components
metabolism and excretion
metabolism aka
biotransformation (enzymatic process)
conjugation makes drug more
water soluble–ionic
reduced as opposed to
oxidized
product of biotransformation
metabolite
Highest concentration of enzymes
GI tract– liver>small intestines>large intestines
liver wants to _______ drug and make it more ______ _______
inactivate, water soluble (inhibit movement through lipid bilayer)
inactive drug or less active drug–pre-activated by liver metabolism
pro-drug (longer half-life or more potent)
drugs carried to liver from GI tract via the
portal vein “first pass metabolism”
metabolite types
active vs inactive
phase I rxn
(redox) does little to change the water solubility of the drug but does significantly alter the biologic properties of the drug–altered pharmacodynamics
Phase II rxn’s
(synthetic rxn) increases drug polarity and water solubility.
phase II rxn’s involve
conjugation with an endogenous substance (i.e. glycine, sulfate)
phase I vs. phase II rxn’s
oxidation vs. conjugation
if drug goes through phase I red/ox rxn’s and is still too neutral for excretion
will go for second pass through liver
if you want to make something polar
conjugate it
no drug has ____% protein binding
zero–given by manufacturer in %
enzymatic system for Phase I rxn’s
cytochrome P450 system (CYP450)–6 isoenzymes metabolize 90% of drugs
CYP450
catalyzes the oxidation of many drugs
*metabolizes 50% of drugs
CYP3A4–CYP450 isoenzyme
CYP450 enzymes located in
smooth ER particularly in hepatocytes (also in small intestine, lungs, placenta, kidneys)
- metabolizes 30% of drugs
CYP2D6
redox is
protons changing molecule
electrons supplied during oxydation by
NADPH –> NADP+
functional groups for redox ex’s
functional groups unmasked or introduced
OH
NH2
SH
COO-
reduced means
it can receive proton
CYP450 drug-drug interaction considerations
Inhibition –> slows metabolism
Induction –> speeds metabolism
So, if drug “inhibits” CYP450 system (particularly CYP3A4)–will get ^ interactions
CYP450 genetic polymorphisms–responsible for variations in drug metabolism
ppl may be: 1. "extensive" metabolizer 2. normal 3. "poor" metabolizer Checked through plasm concentrations
Phase II rxn–named for functional group added
phase II enzyme
Drug ______________> Drug Conjugation
Phase II functional groups added–essentially makes new molecule and very polar
- Glucuronide
- amino acids
- acetyl group
- sulfate ester
- methyl group
come from diet–rate limiting step
drugs may need to go through phase ___ rxn before able to go through phase ___ rxn
I, II
Glucuronidated molecules secreted in ____ and eliminated in ______
bile-
urine
amino acid conjugation with
glutamine or glycine – readily excreted in urine
upper limit in the metabolism rate in any given pathway
capacity limitation of Rate of Metabolism
half-life will be prolonged if
the metabolizing sites are at capacity
*if liver damage/ disease
need to make dose adjustment
Protein poor/ rich diet will ____/_____ drug metabolism
slow/speed
intestinal microflora (anaerobic microbes which colonize gut) are rich in ______
reductases (similar to liver metabolic processes) –may metabolize drugs before their absorbed
principle mechanism of eliminating drug from body
renal excretion–
*( read excretion portion in packet before exam)
excretion=
flitration - reabsorption +secretion
first step in urine production
glomerular filtration–
_______ ______ (arterial blood pressure) drives filtrate into glomerulus of kidney
hydrostatic pressure
allows recovery of drugs filtered by glomerulus
active tubular reabsorption–2nd step
the transfer of materials from the peritubular capillaries into the renal tubular lumen
active tubular secretion
liver secreation of 1 L of bile/ day contributes to
biliary excretion
volatile drugs primarly excreted by
pulmonary excretion (breathed out)–passive diffusion into lungs
extremely _____ soluble drugs, penetrate milk in higher concentration almost without exception
lipid
Milk is _____ acidic than blood
more–will trap weak bases
how long before drug is half concentration from time-point
T1/2
half-life
half-life important for determining
frequency of administration
adjusting dosage according to T1/2, physiological marker, or toxicity
“dosing for effect”
time it would take for a drug to lose half of its effectiveness or efficacy
efficacy half-life–less precise than plasma CO
concentration at which a pharmacologic response first occures
minimum effective concentration MEC
Cmax
peak concentration
maximum amount of drug when ADRs occure at a high enough rate to make it intolerable or dangerous for pt
“upper limit of drug concentration”
dosing the same druge at teh same dose multiple times at regular intervals to build up in body
drug accumulation
time it take to reach the peak concentration
Tmax – time to peak concentration
drug in = drug out
plasma levels stay consistant–use “loading dose”
“steady state” – peaks and troughs
formula used
CL= renal clearance
goal of dosing regimen
one where steady-state conentration is reached as quickly as possible while maximizing benefit and minimizing harm to the pt.
how often a pt needs to take the drug in order to reach a steady state concentration
Css
Tylenol–not NSAID
acetominophen–MAO
acetaminophen and NSAIDs both
inhibit COX-2
Cyclooxygenae COX enzymes convert _____ ____ to _________
arachidonic acid,
prostaglandins
key role in pain, inflammation, cell proliveration, mucus production, fever
prostaglandins
COX1 roles
“housekeeper”
- gastric (^ mucus prod) and renal protection
- COX1 platelets aid in clotting
- kidney profusion
COX1
constitutive
COX2
inducible
increased in response to inflammation
COX2
inflammation symptoms 4–mediated by prostaglandins
pain, swelling, redness, and warmth
inhibiting COX2 will decrease
pain, swelling, redness, and warmth
COX2 in the kidney
helps regulate water and Na excretion–inhibition–>fluid retention
COX 1,2, and 3 involved in _________ synthesis
prostaglandin
unlike NSAIDS, ________ doesn’t inhibit COX in peripheral tissues thus no peripheral ____-_____ affects
acetaminophen-
anti-inflammatory
acetominophen’s blackage of COX is ineffective in presence of ________
peroxides (high in platelets and immune system)
antipyretic properties of acetominophen due to
effects on the heat-regulating center of the hypothalamus –> peripheral vasodilation, sweating –> heat dissipation
only analgesic approved for infants <6 months
acetaminophen
acetaminophen highly metabolized through _____ __ rxns in _____
Phase II,
liver
(toxic metabolite when phase I–hepatotoxic) so need to ask pt what OTCs taking
alcohol is
conjugated–thus drug-drug interactions but not many others for acetamenophen
Know:
drug list
ibuprofen is ________ COX inhibitor
NONSELECTIVE–pain, fever, swelling, inflammation
ibuprofen inhibits
prostaglandin synthesis
ibuprofen more potent than
acetaminophen
onset of action for ibuprofen for pain and fever
30 min–first time dose vs. inflammation (higher dose needed)
ibuprofen ______ binds to albumin (_______%)
avidly,
90-99%
ibuprofen metabolism
extensive and rapid metabolism by liver (CYP450 & v phase II)
ibuprofen should be taken w/ food due to
COX1 inhibition–> ulcers, upset stomach, dyspepsia,
highest cause of gastric ulcer
ibuprofin–discontinue use
strong FDA warning
“black box” warning
prostaglandins important for renal __________, so for vulnerable populations (those with kidney disease)
ibuprofin limit blood flow through kidney–very dangerous–not for normal people
COX in afferent arteriales in kidney
keeps arterial open–disrupted by ibuprofen–> stops blood flow
acetamenophen inhibits only
CENTRAL COX2
cardiovascular risk of ibuprofen
black box warning– ^ risk of thrombotic event from COX II inhibition
2 things to remember w/ ibuprophen–too many ADRs to remember or list
- any drug can cause any symptom
2. any pt can have an allergic rxn to any drug
imp Ibuprophen ADRs
GI tract
kidneys
heart
2 main enzyme systems
3A4
2D6
(2) more acidic than blood–will trap ___ drugs
Breast milk,
amniotic fluid
Principle means of phase II reaction
Conjugation– GLUCURONIDATION
