Pharmacokinetics & Pharmacodynamics Flashcards
pharmacology definition
studies interactions between living organisms and chemicals that affect function
toxicology definition
examines undesirable effects of chemicals on living systems
pharmacodynamics
therapeutic and/or toxic actions of the drug on the body, receptor interactions (agonist, antagonist) concentration-effect component
pharmacokinetics
effect of the body on the drug, dose-concentration component
LADME
pharmacogenetics
effect of genetic makeup on how the drug is handled by the body and affects the body, sequence DNA and predict individual response to drugs ([harmacogenomics)
mathematically describes fate of a drug with a specific dosing schedule, dosage form and route of administration
pharmacokinetics
how is pharmacokinetics useful?
- Predict the effectiveness of different drugs/different dosage strategies
- Predict blood levels in an individual under various conditions
main application of pharmacokinetics
to predict, monitor, and adjust drug regimens to optimize efficacy and safety
LADME
determines how rapid, in what concentration, and how long the drug takes to reach the target organ
liberation, absorption, distribution, metabolism, elimination
_______________ is a function of liberation and absorption
availability
the rate at which drug is absorbed into the body
availability
slope
rate of drug liberation depends on:
- formulation (polymer layers, distribution in formulation)
- dose (more is typically faster)
- ionization state
- environment pH
** last two helps w dissolving
factors influencing absorption
- gastrointestinal factors = food, pH, perfusion, motility, SA, enzymes, microflora, permeability
- physicochemical drug properties = solubility, charge, size, structure
- transporters
- route of administration
these molecules need help getting across lipid bilayers
large, charged molecules
- small, neutral molecules freely diffuse!
slope =
availability
H-H equation
pH = pKa + log10 {[A-]/[HA]}
what does the H-H equation describe?
the propensity for a functional group to carry a proton at a specific environmental pH
H-H example: weak acid
aspirin (pKa = 3.5)
pH < pKa = not ionized
pH > pKa = ionized
H-H example: weak base
morphine (pKa = 7.9)
pH < pKa = ionized
pH > pKa = not ionized
T or F. In general, charged molecules are less readily absorbed than uncharged molecules, which can freely pass through lipid bilayers
T!
T or F. pH = pKa + log (proton donor/ proton acceptor)
F!
proton acceptor / proton donor*
this is the best indicator of total exposure to a dose of a pharmacological compound
AUC = area under the curve
bioavail
what is the bioavailability?
amount of drug dose that reaches circulation
how to calculate bioavailability if given oral dose and intravenous dose AUC
AUC alt route / AUC intravenous route
suppository pros
- rapid absorption
- bypasses first-pass metabolism = reduced side effects
- local effects
- improved compliance = ease of consumption
- relatively safe (pediatric and geriatric use)
what is first pass metabolism
intestinal and liver metabolism reduce bioavailability of an orally administered drug prior to the drug reaching systemic circulation
when we want to calculate the amount of drug absorbed OR the amount of drug making it to circulation, these are considered:
- bioavailability (F) factor: fraction of active dose that makes it to circulation
- chemical (S) factor: fraction of formulation that is active form of the drug
effective dose formula
ED = F (bioavail factor) x dose admin (mg)
what does F=1 mean?
100% availability (intravenous!) therefore, extravascular or incomplete absorption is F<1
bioavailability vs availability
bioavail = only estimates extent and not the rate of absorption
avail = includes rate of absorption
what is the chemical factor
S
considers form of drug (salt or ester) and active ingredient
what is distribution?
the delivery of drug via circulation to extravascular fluids and tissues in the body (target receptor sites, eliminating organs)
- drug is equilibrating and partitioning into tissues
what is drug distribution influenced by?
size of organ
tissue perfusion (blood flow)
drug binding to plasma proteins/tissues
ability of drug to cross cell membrane (solubility)
what is Vd?
volume of distribution (L/kg)
- reflects extent of drug distribution
- size of compartment required to contain total mt of drug in body IF it were present throughout body in same conctn fund in plasma
Vd formula
Vd = total dose (A)/drug conctn (C) x weight (kg)
large Vd
extensive distribution to peripheral tissues
[tissue] > [plasma]
T or F. gentamicin is very water soluble
T! low Vd
warfarin Vd
binds to plasma albumin = small Vd
tricyclic antidepressants Vd
large
- lipid soluble and distribute to brain and fat
factors influencing Vd
drug solubility
- more water soluble = increased plasma conctn = decreased Vd
plasma protrein binding
- if patient had liver cirrhosis and produced less albumin - how would the Vd change for an albumin bound drug?
- decreased PPB = decreased plasma conctn = increased Vd
why is Vd important?
- determines whether dialysis of a drug is likely to be beneficial
- estimates body burden (amt) of drug
- calculates loading dose if drug
total body clearance
- vol of plasma cleared of drug per unit time by processes of metabolism and excretion
> does not indicate how much drug removed - merely the vol of plasma from which the drug removed - organism’s ability to eliminate drug
- total body clearance = metabolic + non-metabolic clearance
- influenced by blood flow and organ function
total body clearance formula
Vd x Kel
what is Kel?
derived experimentally
- plot of concentration vs time of elimination phase of AUC = slope is negative elimination constant
t1/2 =?
0.693/k
what is the drug elimination half life?
time required for the mt of drug in the body or its concentration to fall by 50%
t1/2 formula
[0.693 x Vd] / Cl
elimination half-life: what does it tell you?
- time to steady state: how long do I need to take drug before I can perform TDM?
- rate at which blod conctn falls after drug admin stops: how long do I have to wait to get rid of the drug/xenobiotic from by body?
- estimate appropriate dosing interval: how frequently do I need to take the drug to keep my plasma conctns within the therapeutic range?
rate in = rate out
steady state
in practice, steady state is assumed to be reached in ___ half lives
5
what is steady state influenced by?
drug half life
and
dose
** time to achieve steady state influenced by half-life and syteady state conctn determined by dose and frequency of dose **
maintenance dose
amt of drug administered to maintain a desired steady state drug conctn in the body
TDM candidates
- narrow therapeutic range
- clinically dangerous or difficult to interpret for over or underdoing
- high biological variation
- conctn proportional to clinical effect
- avail of a standardized, reliable assay
- conc changes with polypharmacy, inhibition, induction, diet
how to properly perform TDM
- drug should be at steady state
- should be collected at a trough or peak for consistent eval
- if drug too low/high = dose adjustments necessary = can use PK to approximate an appropriate initial dose or adjusted dose
FIRST ORDER ELIMINATION
- rate of drug clearance is proportional to drug conctn
- fraction or % of total drug removed at any instant in time is constant
- slope = -kel
zero-order elimination
- rate of drug clearance or amount of drug eliminated per unit time is CONSTANT regardless of drug conctn
> constant amount of drug, instead of proportion is eliminated per unit time - drugs that saturate elimination mechanism (enzyme/transporter)
- ex: alcohol, phenytoin, aspirin, etc.
hepatic elimination of drugs
- cell dissocisyion (free drugu)
- protein dissociation
- hepatocyte uptake
- metabolism (into detergents or salts or conjugare to make more water-sol)
- biliary excretion
- bacteria hydrolysis
- enterohepatic re-circulation
renal elimination of drugs
- passive glom filtration
- active proximal tubular secretion (OAT = weak acids; OCT = weak bases)
- passive distal tubular reabsorption (non-ionized)
non-volatile, water sol, low MW drugs
factors affecting renal excretion
drug properties
plasma protein binding
fluid intake (flow)
urine pH
other drugs
kidney function
T or F. Charged molecules are easier t clear
T!
what alters pharmacokinetics?
lots!
body fat
intestinal permeability
renal funtion
organ perfusion, etc.
how does bioavailability change between peds and geriatrics?
peds
- decreased gastric acidity
- prolonged gastric residence time
- slower intestinal motility
- decreased bile salts
- good absorption of pen, amp and digoxin
- poor absorption of phenobarbital, phenytoin, gabapentin
- poor transporter function
- increased skin permeability
gers
- delayed gastric emptying
- decreased absorption surface
- decreased GI motility
how does distribution change between peds and geriatrics?
peds
- increased total bod water to body fat ratio = increased Vd for hydrophilic drugs
- decreased binding capacity of albumin
- decreased alb and alpha1 acid glycoprotein
- high bili displaces drugs
gers
- dec total body water to body fat ratio = decreased Vd for hydrophilic drugs
- decreased plasma protein binding increases free drug conctn in plasma
how does clearance change between peds and geriatrics?
peds
- immature renal function
- unique metabolic pathways (theophylline => caffeine)
- immature liver function (CYP P450 and UT activity)
gers
- slight decline in renal function
- slight decline in hepatic function
- phase I metabolism (reduced or no change)
- no change in phase II
these are often not considered by practitioners but may contribute significantly to therapeutic or adverse side effects
metabolites (of active drug)
what are xenobiotics?
organic compounds that are foreign to the body such as drugs, industrial chemicals, pesticides, pollutants, alkaloids, and toxins produced by mold, plants, and animals
most pharmacologically active molecules are ______________ and remain ___-________ or only partially at physiological pHH
lipophilic and non-ionized
> means that even after filtration in kidneys, can still be reabsorbed in the body
a means of converting molecules into substances that are easily more excreted
drug metabolism
biotransformation
the enzymatic transformation of molecules by fuctionalization (Phase I) and/or conjugation (II) rxns into molecules that are polar and water soluble
phase I rxn
introduction, exposure or modification of specific chemical functional group
- ex: redox rxns
phase II rxn
conjugation of small endogenous molecules (ex: glucuronic acid)
- makes something more water sol
T or F. Water sol compounds of phase I rxns still require conjugation to be efficiently eliminated
T!
T or F. Decreased polarity reduces tubular reabsorption in kidney = excretion of compounds
F! It is increasing polarity that results in reduced reabsorption ; decreased polarity = increased reabsorption
what is the main goal of metabolism?
increase the hydrophilicity to dissolve xenobiotics in urine for efficient elimination
acetaminophen toxicity
- effect of metabolism = toxic components are the metabolites
- CYP2E1 converts APAP to toxic free radical, NAPQI
- NAPQI destroys liver cells unless conjugated with glutathione
- depleted glutathione = damage
the major organ responsible for biotransformation of xenobiotics
LIVER
but every tissue has ability to metabolize compounds
major enzymes for biotransformation
- cytosolic like acetyltransferase
OR
- membrane-bound to ER like CYP enzymes and glucuronosyltransferase
examples of phase I rxns
oxidation
- cytochrome P450 or CYP enzyme system
- alc dehydrogenase and aldehyde oxidase
- N- and S-oxidation
reduction (aldehydes to primary alcohols)
- hydrolysis (esterases, amidases)
examples of phase II rxns
glucuronidation
sulphation
acetylation
methylation
glycine conjugation
glutamine “
glutathione “
most increase water sol of xenobiotic
effects of benzodiazepines
anxiolytic, sedative, and anticonvulsant properties
“-ams”
compared to tertiary amine, 2ry amines more potent inhibitors of ____________ reuptake and less potent inhibitors of reuptake of __________ into nerve terminals
noradrenaline; serotonin
the 2ry and 3ry amine tricyclics also differ markedly in their ability to block ___________, ____________, and _-___________ receptors
histaminergic, muscarinis, alpha-adrenergic
> so side effects associated w blockade of these receptors differ
hydroxy metabolites important with respect to ________________
cardiotoxicity
2ry amines examples
desipramine
nortriptyline
3ry amines
imipramine
amitriptyline
T or F. SSRIs are safer than Tricyclic antidepressants
T! don’t matter if been metabolized into other forms
SSRIs (PK/PD)
- fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil)
- inhibit reuptake of serotonin from nerve terminals
unlike metabolites of tertiary amine tricyclics, metabolites of SSRIs also selectively inhibit the reuptake of serotonin (and/or are very weak noradrenaline reuptake inhibitors)
CYP enzyme system components
hemoprotein
flavoprotein
heat stable, lipid component
CYP Enzyme system: hemoprotein
- iron protoporphyrin IX = heme group
- serves as substrate and O2 binding site of enzyme system in which heme iron underoes cyclic REDOX that is mandatory for catalytic function
> terminal oxidase component of electron transfer system present in ER
CYP Enzyme system:flavoprotein
NADPH-cytochrome P450 reductase; NADPH-cytochrome c reductase
- acts as electron carrier shuttling electrons from NADPH to CYP substrate complex
- binds to cofactor NADPH
CYP Enzyme System: heat-stable, lipid component
- may be needed for substrate binding, facilitation of electron transfer or providing a template for the interaction of CYP and NADPH-cytochrome P450 reductase molecules
- HOLDS everything where it’s supposed to be positioned in space
CYP 450 (11)
steroid 11 B-hydroxylase
CYP 450 (17)
steroid 17 a-hydroxylase
CYP 450 (21)
steroid 21-hydroxylase
nomenclature of CYP genes
CYP with arabic number = family
letter after is the subfamily
arabic number after = individual gene
corresponding gene products - mRNA, cDNA and enzyme are not italicized
variations in drug metabolism can be divided into 4 categories
- host factors: diet and disease states
- genetics
- enzyme induction by exposure of CYP enzymes to drugs, endogenous compounds o environmental agents
- inhibition of CYP enzymes by drugs, endougeous compounds or environmental agents
T or F. Host factors may inihibit or induce CYP mediated metabolism depending on dietary items and diseases processes in question.
T
Brassica veg
increases CYP 1A2
- brocolli, cauliflower, etc.
Apiaceous vegs
decrease CYP1A2 activity
- carrots, celery, etc.
grapefruit juice
inhibits CYP3A4 activity
what does aging do to CYP enzymes?
slight decrease in some oxidation rxns catalyzed by them
grapefruit juice can inhibit ________, mustards can induce _________.
CYP3A4 and CYP1A2
the study of genetically determined variation in drug metabolism
pharmacogenetics
what is pharmacogenomics?
customization of dosing to match a patient’s specific genetic profile
mutations that occur in at least 1% of population
polymorphisms
many polymorphisms are functionally significant, often resulting in:
decreased activity
increased activity
no activity
no change in activity
extensive metabolizer
- wild type
- person who metabolizes a probe drug at a rate similar to that of most of the popln
poor metabolizer
person who metabolizes a probe drug at a rate slower than most of the population
consequence: lack of response due to inability to convert prodrug to its active form (codeine to morphine) or it may result in excessively high levels of the parent drug such that toxic side effects develop
ultra-rapid metabolizer
person who metabolizes a drug more rapidly than most of the popln due to presence of multiple copies of CYP2D6 genes
consequence: these people fail to respond to conventional doses of drugs; they may be suspected of non-compliance when in fact they require very high doses to achieve therapeutic effects
how do we determine whether patients are PMs, EMs, and URMs
genotyping (predict the optimal dose using genetic info) and phenotyping (predict dose using metabolite/parent drug ratio in urine)
where is CYP2D6 expressed?
liver, intestine, kidney, brain
this metabolizes ~30% of drugs currently in clinical use
CYP2D6
substrates of CYP2D6
codeine
amitriptyline
Fluoxetine (Prozac)
Paroxetine (Paxil)
T or F. CYP2C92 and CYP2C93 show reduced rates of metabolism toward substrates compared to CYP2C9*1
T
how is warfarin administered?
as a recemate (S-isomer = 5X more potent than R as anticoag)
R-warfarin is metabolized by….
CYP1A2, 2C19, and 3A4
S-warfarin metabolized by…
CYP2C9
what is enzyme induction?
- occurs through action of drugsm endogenous compounds or environmental agents
- can increase CYP enzyme expression by increasing synthesis, decreasing degradation, activating pre-existing components of metabolic system
- lowers blood levels of parent drug (parent is metabolized more quickly than usual)
- lowers blood levels of parent drug (parent metabolized more quickly than usual)
