Unit 1 Flashcards
define pharmacology
study of interactions of drugs (chem subs) with biological systems
define pharmacotherapy
"dosage regimen" involves section of the right drug in the right dose to interact with the right drug target to produce the desired therapeutic effects: -prevention -diagnosis -treatment -cure of a particular disease
pharmacokinetic and pharmacodynamic principles
allow the determination of the relationship between the dose of the drug given the patient, the plasma concentration (Cp) that results from the dose, and the clinical effects that will result from that plasma conc
drug effects and plasma conc
therapeutic or toxic, they’re directly related to each other for most drugs in clinical use
graphs of Cp vs time determine drug pharmacokinetics
MEC
minimum effective conc
can be determined for both the desired (therapeutic) response and any adverse responses
single or first dose administration concepts
- onset of effect: time to reach MEC
- duration of action: time above MEC
- therapeutic window (AKA therapeutic index): difference in Cp between the desired and adverse response MEC
goal of pharmacotherapy
when multiple doses are administered to reach and maintain plasma con’s at steady state within the therapeutic window to produce the desired response with a minimum of toxicity
multiple or maintenance dose administration concepts
- steady state: condition exists when the rate of drug administration (rate IN) equals the rate of drug elimination (rate OUT)
- time to steady state: attained in 4-5 half-lives when maintenance doses are administered at constant interval
- steady state conc: average Cp after steady state achieved
- fluctutations in steady state Cp: related the number of half-lives in the dosing interval (time between doses)
dosage regimen (for multiple dose administrations)
key element in pharmacotherapeutics
designed to ensure that the desired steady state drug level (Cp ss (avg)) is maintained within the therapeutic window by balancing the rate of drug elimination with the prescribed rate of drug administration
4 things to select for with dosage regimen:
contents of a prescription: select drug and dose select route of administration select dosage frequency select duration
pharmacodynamics- mech of action
what the drug does to the body
enables identification of drug target and therapeutic category
drug target
commonly a membrane or intracellular receptor, an enzyme in a critical biosynthetic pathway, or a membrane transport protein
drug actions
enhance or block the normal physiology of the various organ systems, depending on pathophysiology
NO unique actions
physiology vs pathophysiology vs pharmacology
student learns physiology to identify potential target for drug action
pathophysiology- determine how the target should be manipulated (enhanced or blocked)
pharmacology- select appropriate drug to induce manipulation
pharmacokinetics: what the body does to the drug
info regarding drug absorption, distribution, and elimination that is necessary for designing dosage regimens
absorption and distribution affects route of:
administration
bioavailability
F
how much of the dose of the drug will reach its target in the body
time to peak effect
TMax or Cmax
how fast does the drug reach its target
volume of distribution
Vd
what dose (mg) to obtain desired plasma conc Cp- mg/L
absorption
passage of drug from the site of drug administration (AKA route of administration) into blood
distribution
movement of the drug from the bloodstream to the tissues, where it can access targets for both therapeutic and side effects of the drug
includes considerations of drug-protein binding, passage across blood-brain barrier or placenta, and selective accumulation affecting drug efficacy or toxicity (lungs, bone, ear, kidney/urine, saliva, breast milk)
route of administration
site of application of the drug into or on the patient
systemic vs topical effects from drug administration
systemic- absorbed into bloodstream and distribute to sites of action in body
topical- mostly remain at site of application for local action
elimination affects:
frequency of administration
-how long the drug will stay at its target in the body (duration of action) (half life)
major organs of elimination
Liver- metabolism
Kidney- excretion via urine
rate of elimination
half life
determines length of time the drug will remain in the bloodstream to exert its clinical effects
adverse rxn
predictable from mech of action
2 type of dose
loading dose LD
maintenance dose MD
dose equation
maintenance dose equation
dose = Cp x Vd or Cp = dose / Vd
MD / tau = Cpmax x CL
In = Out
Tau= dosing interval CL= clearance
pharmacokinetics of elimination- half life
allows quick rule of thumb estimates of:
time for elimination of drug from plasma
time to reach steady state plasma drug levels following multiple doses
fluctuations in plasma levels between doses
drug effect vs plasma level
direct correlation
routes of absorption
local routes: site of action receptors
- inhalation
- dermal
- aural, nasal, throat, vaginal, ocular/conjunctival
systemic: absorbed through tissue reservoirs or liver oral rectal IV transdermal sublingual buccal inhalation subcutaneous intramuscular
4 factors influencing drug membrane passage
molec size (can be affected by binding plasma proteins; smaller crosses better)
lipid solubility (set by oil:water partition coef; increasing increases membrane passage)
degree of ionization (affected by tissue pH, influences lipid solubility; unionized = greater crossing)
conc gradient (created at site of admin)
drug permeation across cell membrane routes
passive diffusion- water soluble drugs through aqueous channels
passive diffusion- lipid soluble drugs via hydrophobic bonding with membrane lipids
active transport and facilitated diffusion- via membrane carrier molecs (p-glycoproteins)
most common mech for drug passage across a membrane
lipid diffusion through membrane itself
graph of Cp vs Time
determines 4 pharmacokinetics parameters-
absorption, distribution, metabolism, elimination
area under curve shows extent of absorption
bioavailability F
F = AUC(oral) / AUC (IV)
-Expressed as % of IV dose reaching plasma by the oral route
-used for dosage adjustments when route is changed
F = 100% for IV, no absorption step is involved
other routes of systemic drug action: Intramuscular, subcutaneous, sublingual, inhalation
-F usually approaches ~100% (~75% -
bioavailability F
oral administration
F varies 0-100% depending on:
survival of drug in GI environ (acidity, digestive enzymes)
ability to cross GI membranes (small, uncharged, lipid soluble cross best)
efficiency of drug metabolism (GI/liver)
–first pass effect requires you to up the dose for same drug conc
first pass effect
wide drug and interpatient variation
needing to pass through liver (and its metabolic processes) to get to the plasma
oral--> intestine --> hepatic portal vein --> liver biotransformation (metabolism) --> systemic circulation
ways to bypass 1st pass effect
IV administration
rectal dose (alcohol enema)
sublingual/buccal
ex first pass effect is best described as:
hepatic or gastric metabolism of a drug prior to entry into the systemic circulation
estimate rate of absorption
Tmax and Cpmax
rate of absorption from the oral route
for clinically useful drug levels Rate of absorption Rabs is at least 10x greater than Rate elim
Drug formation can be a factor in rate of absorption
- increased for liquid preps or rapidly disintegrating tablets (vs standard tablets)
- decreased with enteric coated products or sustained release preps (time to peak slowed and Cpmax blunted– bioavailability UNAFFECTED)
rate of absorption from parenteral routes
rate of onset of effected determined primarily by route rather than individual drug characteristics for soluble formulations
IV = inhalation > intramuscular > subcutaneous > oral
insoluble formulations/suspensions are designed to slow rate of absorption and extend duration of action
determining equivalency of drug products
major equivalency test- required by FDA for generics is bioequivalency
generic drug product is bioequivalent to brand name drug product if:
-rate of absorption AND extent of absorption (AUC- bioavailability) of active drug in generic formulation is within set limits
bioequivalent = therapeutic equivalents
general factors affecting drug absorption
drug solubility in aqueous environ
- formulation must have hydrophilicity to dissolve
- molec must be lipophilic to cross lipid membranes
rate of dissolution
- solid for oral dosage formulation
- suspended particles for parenteral formulation
conc of drug at site of admin (gradient)
circ at site of absorption (disease or exercise effects)
area of absorbing surface (stomach vs intestine vs lungs)
routes of drug elimination
urine
feces
breast/sweat glands- milk, sweat
expired air
ex type of drug with greatest oral viability:
large hydrophobic drugs, yet soluble in aqueous solutions
oral route absorption
relatively slow onset of action; variable bioavailability
absorption from GI tract primarily via lipid diffusion; favored with less ionization BUT most drugs absorbed best from SI due to large SA
increase GI motility increases rate of absorption; reaches SI faster
-food slows absorption by delaying gastric emptying; potential for drug-food interactions
- take on full stomach to protect stomach
- take on empty stomach to protect drug
stomach and SI absorption
better extent of absorption in stomach
better rate of absorption in SI
dissolution delayed until reaching the more basic pH of SI
pros and cons of controlled-release preparations
advantages:
decrease number of daily doses
maintain drug affect overnight
eliminate toxic peaks or sub therapeutic troughs
cons-
interpatient variations with Cp
dosage form failure
IV drug administration
most rapid onset of action (100% bioavailability)
most direct route of admin
- no membrane passage factors
- accuracy-immediacy of drug delivery exceeds all routes
-used for drugs with narrow therapeutic index
bypass absorption barriers- increased infection potential
most hazardous route- can reach toxic levels rapidly and reversal of effect often difficulty
intramuscular route
rapid onset (5-10 min) and approaching 100% bioavailability
absorption may be erratic and incomplete if drug solubility in soon is limited (ex. diazepam)
depot forms in oil or suspensions exhibit slower, more sustained absorption (hours-days)
-onset delayed as release or dissolution step must occur before moles is absorbed
ex. contraceptives, anti-inflammatory glucocorticoids
subcutaneous route
often utilized for slower, constant rate of absorption
bioavailability near IV ~100%
absorption altered by varying particle size, pH, protein complexation, vasoconstrictor, pellet implantation
drugs must be non-irritating
injection vol more limited than IM route
ex. insulin preparations
- injection of soln provides relatively rapid onset of action
- injection of suspension slows onset- increases duration
sublingual-buccal route
onset of action within minutes
high bioavailability
-drains into Superior Vena Cava, so no first-pass effect
useful if drug is lipid soluble and potent (
rectal suppository or solution route
non-rapid onset and variable bioavailability- generally greater than oral
useful if vomiting, unconscious, post-GI surgery, presence of GI irritation, or uncooperative patient
patient acceptance is not high
transdermal patch
application to skin for treatment of SYSTEMIC conditions
prolonged drug levels to provide extended duration of action
hours-week
first pass metabolism is avoided
- increased bioavailability
- plus reduced potential for adverse rug rxns (ADRs) related to hepatic actions
ex. contraceptives, nitroglycerin, fentanyl, clonidine
patient in ER with drug overdose
best route of administration of antidote?
intravenous
which route of drug administration has the most rapid onset of action?
inhalational
but also intravenous
inhalation route for local effects
molecs in suspension (aerosol/microparticles)
applied at site of action in lungs
designed to maximize local actions
effects depend on particle size
dermal local route
application via skin or mucous membranes for treatment of local conditions (inflammation, infection)
generally minimal systemic absorption
bioavailability summary
100% IV
75-100% IM, SC, SL, inhalation, transdermal
tissue environ is non-destructive
0-100% oral; variable due to GI and 1st pass metabolic effect
speed of onset of drug effect summary
time to peak effect
most rapid (sec-min): inhalational, IV
intermediate (5-15 min): sublingual, IM, SC, buccal
slower (15-30 min): oral
slowest (hours): transdermal, oral (enteric coated and sustained release), depot forms of IM and SC
duration of action summary
time above MEC
special drug formulations:
delay drug molec release
slow drug absorption from some routes
extend duration of action (independent of t1/2)
charged drug molecs and BBB
permanently charged molecs cannot cross blood brain barrier
physiologic factors influencing drug distribution
sites requiring drugs to pass through cells, not between (whether there are gap junctions)
pH of fluids in compartments
lipid solubility of non-ionized form
drug binding to plasma proteins (only free drug is diffusible)
tissues with tight junctions
limit movement of certain drugs (large, protein bound, ionized, high water solubility)
GI mucosa- negligible absorption (have to go through cells)
Blood brain barrier and placenta- limited distribution
renal tubules- reduced absorption back into blood and increased urinary excretion
true about blood brain barrier
drugs can cross BBB through specific transporters
lipid soluble drugs readily cross the BBB
weak acids vs weak bases
weak acid -COOH
most readily cross when in an acidic environ (pH RCOO- + H+
weak base -NH3+
R-NH3+ R-NH2 + H+
most readily cross when in basic environ (pH > pKa)
non-ionized forms are more readily absorbed
ionized forms are “trapped”
pKa
the pH where the amount of an unprotonated substance = amount of protonated substance
when pH = pKa
HA = A-
BH+ = B
Henderson Hasselbach Equation
pH - pKa = log (non-protonated/ protonated)
10^ (pH - pKa) = (unprotonated / protonated)
allows determination of % ionized
allows predictions of pH at which majority of drug will be ionized and whether absorption or trapping is favored
ex. aspirin is weak acid with pKa of 5.4. What % of a given dose will be in the ionized form (water-soluble) at plasm pH of 7.4?
about 99%
10^ (7.4-5.4) = 100/1
5.4 to 7.4 means 100 fold change
ex Hydrochlorothiazide is a weakly acidic drug with pKa of 6.5. If administered orally, at which of the following sites of absorption will the drug be able to most readily pass through the membrane?
mouth pH 7.0 stomach pH 2.5 duodenum pH 6.1 jejunum pH 8.0 Ileum pH 7.0
want pH to be less than pKa to become -COOH uncharged
leaves stomach and duodenum
stomach is best answer- drug will cross membrane best where most of it will be unionized; better EXTENT of drug absorption
SI (due to SA) changes RATE of absorption, not extent
ion trapping
total conc of drug is greater on one side of lipid barrier where extent of ionization is greater
clinical significance of ion trapping
alteration of urinary pH to trap weak acids or bases and hasten renal excretion (plasma has buffering capacity)
-alkalinization of urine can trap weak acid aspirin in overdose situations
greater potential to concentrate basic drugs (like opioids) in more acidic breast milk
forensic pathology- weak base toxins are found concentrated in the acidic contents
effect of protein binding on drug disposition
only free drug is diffusible, so protein binding:
- reduces conc of active, free drug
- hinders metabolic degradation and reduces excretion (dec elimination and incr half life)
- decreases Vd
- decreases ability to enter CNS through BBB
but- protein-binding rarely of clinical concern unless changes occur after therapy has been started
protein-binding displacement interactions
administration of 2nd drug displaces 1st drug from binding sites, increasing free levels of 1st drug
-often small and transient increase as free drug distributes to tissues and subject to metabolism and excretion
very unlikely to be of clinical consequence unless:
displaced has narrow therapeutic index
displacing drug is started in high doses
Vd of displaced drug is small
response to drug occurs more rapidly than redistribution
ex effects of increasing the binding of a drug to plasma proteins
decreases plasma conc of active drug
dec elimination of drug by liver metabolism and kidney excretion
inc dose needed to achieve therapeutic effectiveness
inc possibility of adverse interactions with other drugs that bind plasm proteins
rate of distibution
most drugs absorbed into and eliminated from a central plasma compartment
rate of distribution seldom of clinical consequence
-slow distribution out of plasma can led to “bolus” toxicity for drugs given IV
extent of distribution
Vd in L/kg
size of compartment necessary to account for total drug in body if present at same conc in body as Cp
is an apparent vol that represents the relationship between dose of a drug and the resulting Cp
we’re ok not knowing conc of drug in tissues because response of drug is proportional to Cp
determination of Vd
single dose of drug (Ab) is administered IV and Cp at time 0 (C0) is determined and Vd is calculated
Vd= amount of drug in body (Ab) / Cp
ex. bolus or slug effect is most likely to be seen when drugs are administered via:
IV
Cp vs Vd relationship
inverse relationship
the more of the dose that remains in the plasma, the less the Vd
vol of compartment vs Vd for drugs
plasma/blood 3-5 L
drugs highly bound to plasma proteins:
Heparin 4 L, Warfarin 10 L
EC water 12-15 L
drugs highly water soluble that don’t enter cells:
ibuprofen 11 L, Gentamicin (22 L)
Total body water 42 L
drugs that freely enter cells (small molecs): Lithium 46 L, ethanol 42 L
other compartments > 50 L
drugs highly lipid soluble sequestered at tissue sites:
amitriptyline 1050 L, Fluoxetine 2450 L
ex new drug is in phase 1 testing and has Vd of 3-5 L in a 70 kg patient. Vd value most consistent with:
drug is highly bound to plasma proteins
could also be highly lipid soluble and use a lipoprotein
clinical use of Vd
Vd will vary between patients depending on: body size (based on weight) composition (fat vs lean; more fat = lower Vd) changes in protein binding determine loading dose determine effect on Cp
general characteristics of drug metabolism
lipid soluble compounds converted to more water-soluble (more polar) compass to be more readily excreted
liver is primary organ of drug metabolism lung 30% kidney 8% intestine 6% skin 1% placenta 5%
most common outcome of drug metabolism:
> 95%
inactivating-detoxifying process forming rapidly excreted and pharmacologically inactive metabolites
less commonly seen outcome for drug metabolism:
morphine
inactive prodrug to active drug
toxic metabolite
ex drug metabolism usually results in a product that is:
less likely to distribute intracellularly
more water soluble than parent drug
phase 1 vs phase 2 rxn types
Phase 1:
oxidations
-hydrolysis
-reductions
Phase 2:
conjugations
phase 1 vs phase 2 enzymes
1: CYP450
esterases-amidases
reductases
2: transferases
phase 1 vs phase 2 genetic polymorphism
1: significant
2: significant
phase 1 vs phase 2 induce-inhibit
1: significant
2: possible- less
phase 1 vs phase 2 development patterns
1: variable
2: variable
phase 1 vs phase 2 age changes
1: decrease in 1/3
2: minimal (want to use this with older patients)
phase 1 vs phase 2 satiability:
1: minimal
2: substantial
phase 1 biotransformations
renders the molec more water soluble
drug metabolite can then undergo conjugation in a phase 2 rxn
rxns incl: oxidation, reduction, hydrolysis
phase 2 biotransformations
conjugations
endogenous substrate combines with:
-pre-existing or metabolically inserted func group (via phase 1 rxn) on the drug
-substrates are high-E and in limited supply; increased likelihood of depletion; zero order kinetics
forms highly polar (water soluble) conjugate that is readily excreted via urine
phase 2 rxn may rarely precede phase 1 runs
rxns include: glucouronidation, acetylation, glutathione/glycine/sulfate conjugation
ex drugs metabolized by CYP 460 enzyme they:
require molec O2
generally highly lipid soluble
usually become more highly oxidized
metabolized in smooth ER
phase 1 genetic polymorphisms
exist; variations in activity of certain drug metabolizing enzymes among patients
amplichip test: to detect polymorphisms in CYP2D6/2C19
classified at extremes: ultra-rapid (UM) or poor metabolizers (PM)
clinical significance depends on whether drug metabolism is detoxifying or activating
genetic polymorphisms with detoxifying and activating rxns
detoxifying rxns:
PM: CYP2D6 increased antipsychotic drug toxicity
UM: CYP2D6 nonresponse to antidepressants
Activating rxns:
PM: CYP2C19 dec efficacy of PPIs for PUD
PM: CYP2D6 insufficient analgesia with codeine
UM: CYP2D6 codeine intoxication due to rapid metabolism to morphine
ex old female underwent total hip arthroplasty
post-procedure pain adequately managed with morphine; discharged with tylenol #3 prescription (acetaminophen-codeine). within 24 hrs pain became intolerable. Which CYP450 genetic polymorphism is most likely she didn’t respond to codeine analgesia?
poor metabolizer for CYP2D6
phase 2 conjugations- general
drug or drug metabolite is coupled/conjugated to highly energetic endogenous reactant provided by a coenzyme
limited supply of reactants renders phase 2 rxns more easily saturable (zero order elimination kinetics) than phase 1
operative enzymes known as transferases
product most often highly water soluble and readily excreted (exception N-acetylation)
ex a phase 2 drug metabolism rxn:
will be less likely to decline in activity with aging than phase 1
rxns
more likely to reach saturation Vmax
not dependent on O2 and NADPH as cofactors
doesn’t have to be preceded by phase 1 rxn
ex local anesthetics such as lidocaine or bupivacaine are metabolized in the liver by:
amidases
ex what phase 2 rxn makes phase 1 metabolites readily excretable in urine?
sulfation and glucouronidation
enzyme induction of drug metabolism
increase in activity in response to certain compds
observed with > 300 different compds (inducers): cigarette and marijuana smoke air pollutants industrial chemicals DDT numerous drugs
most is known about induction of CYP450 enzymes, but some forms of phase 2 enzymes (UGT) are also inducible
mech of induction
mainly due to increased synthesis of enzyme protein, but decreased turnover also occurs
generally requires 48-72 hours to see onset of effect
inhibition of drug metabolism
occurs with many drug metabolizing enzymes
-phase 1 more prone than phase 2
variety of mechanisms: inhibit enzyme synthesis inhibitor can be competitive substrate allosteric inhibitor formation of a metabolite -destroys enzyme -forms tight complex inhibiting further activity
metabolic drug-drug interactions
most occur via effects on CYP450 sys; inhibitors and inducers of specific P450 isozymes are known
effects most obvious when drugs are given orally via 1st pass effect
metabolic inducers vs inhibitors
inducers- increase metabolic rate
inhibitors- decrease
clinical effect is dependent on whether metabolic rxn is:
inactivating (detoxifying; most common 95%)
activating
therapeutic consequences of induction
maximal effects of enzyme induction usually seen in 7-10 days; require similar time to dissipate
induction by one agent may increase clearance of other drugs
production of pharmacokinetic tolerance:
induction by a drug of its own metabolism: phenobarbital-carbamazepine
clinical implications (of resulting drug interactions) of induction
reduced therapeutic effect if inactivation rxn is accel
increased toxicity if activation rxn in accel
increased toxicity if toxic metabolite is produced
drug-drug interactions
oral contraceptives plus rifampin
rate in = rate out
drug dose / freq = Cp x CL
rate in unchanged = Cp x (increased CL due to Rifampin), which means lower Cp for Oral contraceptive and possible unplanned pregnancy
therapeutic consequences of inhibition
inhibition of metabolism can occur as soon as sufficient hepatic conc is reached (generally within hours)
time to effect on steady state Cp is dependent on inhibited drug’s half life
inhibition by 2nd drug of 1st drug metabolism gives dec CL of 1st drug gives higher Cp gives inc toxicity
if an activating metabolic rxn (less common) is inhibited, then reduction in therapeutic effect
drug-drug interaction
lipitor plus erythromycin
rate in = rate out
lipitor / frequency = Cp x CL
rate in unchanged = Cp x (dec CL due to Erythromycin),, so inc Cp for Lipitor and inc risk for myopathy
clinically relevant inducers and inhibitors
inducers: PP CREST phenobarbital phenytoin carbamazepine rifampin *ethanol *St. John's Wort *Tobacco Smoke (not nicotine)
inhibitors: FACE HOG fluoxetine (other SSRIs) azalea antifungals *cimetidine erythromycin/clarithromycin HIV protease inhibitors *omeprazole *grapefruit juice
*available without prescription
zero order kinetics
amount of drug eliminated per unit time is constant
most often due to saturation of hepatic metabolic processes (esp phase 2 conjugations)
seen with a few drugs at therapeutic doses and many at toxic doses
saturation unlikely to occur with renal excretory process, but maybe the liver
biological factors influencing drug metabolism
diet and nutritional factors- little known about role in humans
sex- some evidence for differences
age-
perinatal: some enzyme sys’s are not well developed at birth
neonatal: variable dev patterns
old age: decrease in phase 1 CYP450 with aging (1/3 of patients)
genetic factors- inter individual and interethnic differences
disease states
renal clearance mech
filtered drug from glomerulus pH dependent passive reabsorption active secretion (back to ureters)
trapping drug in urine increases its elimination
urine 1mL/min
ex alkalinization of urine by giving bicarbonate is used to treat patients with pentobarbital (weak acid) overdose. What best describes the rationale for alkalinization of urine here?
to reduce tubular reabsorption (back into blood) of pentobarbital
biliary-fecal excretion
blood and drug go through liver
excretion via bile and bile duct into intestines to be excreted via feces
enzymes can interfere and cause enterohepatic recycling
ex the addition of glucuronic acid to a drug molec:
increases its water solubility
usually leads to inactivation of the drug
excretion into breast milk
most drugs do cross into breast milk, but usually at low levels
resulting infant plasma level for most drugs is substantially below therapeutic level
desynchronize breastfeeding and peak milk-drug conc’s
- breastfeed at end of dosing interval
- administer drug immediately after nursing
- administer a dos prior to infant’s longest sleep time
- shorter nursing periods (fat (and drug) content of milk increases during feeding period)
pulmonary route of excretion
gases, alcohols, and volatile substances (simple diffusion)
parent drug is usually cleared without metabolism
rate for highly soluble gases dependent on respiratory rate
rate for poorly soluble gases (N2O) depends on blood flow
sweat excretion
responsible for certain skin reactions to ingested drugs
saliva excretion
accounts for dug “taste” noted after IV administration
if drug excreted in saliva is then swallowed, same fate as oral administration
hair excretion
responsible for cancer chemotherapy-induced hair loss
note- drug assays can be performed on samples from all routes of excretion
ex regarding termination of drug action:
hepatic metabolism and renal excretion are the 2 most important mech’s involved
ex the best-documented and quantitatively the most clinically important mech by which drug-drug interactions occur is via:
inhibition or induction of the metabolism of the drug
also interference with renal tubular secretion of the drug
first order kinetics
rate of elimination is proportional to the conc of the Cp
-rate of elimination is fastest when you have the most- half lives
most clinically utilized drugs are eliminated by 1st order kinetics when given in therapeutic doses
biological processes for drug elimination are 1st order processes
graph of drug elimination
Cp vs time
-steeper sloper means greater elim rate
ln Cp vs time
- straight slope; Ke (elim rate)
- y-intercept is ln Cp 0
half life
characteristic of first order kinetics
constant fraction of drug is eliminated per time and is independent of the total amount present
time required to eliminate half of drug t 1/2 = 0.693/ke
- time for drug to be eliminated= 4-5 half lives
- time to reach steady state when drugs are administered continuously- 4-5 half lives (use loading dose when you can’t wait 4-5 half lives)
- degree of fluctuations in Cp between doses (number of half lives in dosing interval Tau / t1/2)
ex if Cp of a drug declines with first order kinetics, it means:
the half life is the same regardless of Cp
the rate of elimination is constantly changing as the Cp changes
clearance
L/hr or mL/min
CL = Vd x ke
theoretical def: Vd which is completely cleared of drug in a given period of time by combined tissue processes such as kidney and livery and others
proportionality constant that makes Cp at steady state equal to the ke
MD/tau = CL x Cp (ss)
clearances from each organ are additive
ex half life of a drug is dependent on:
clearance (inverse)
Vd (direct)
hepatic clearance
varies with blood flow to liver
-for high extraction drug- changes will have major influence on CL
low extraction’s do not
renal clearance
varies as kidney func varies (serum creatinine –> CrCL used as an estimate of GFR)
changes in renal func will alter renally eliminated drug CL
necessitates dose changes to prevent drug accumulation “renal dosing”
summary- calc pharmacokinetic parameters from ln Cp vs time graph
ke Cp0 t1/2 Vd F
ke: from slope of beta elimination phase
Cp0- from extrapolation of line to time 0
t1/2- from 0.693/ke
Vd- from dose/ Cp(at a time)
from Cp vs time:
F from AUC
effect of dose on Cp ss
time to reach steady state plateau is related to the half life of a drug; independent of drug dosage
increasing maintenance dose will not reach steady state sooner, but will cause Cp ss to be higher when ss is reached
use of loading dose
to attain desired steady state Cp sooner, give an LD then follow with normal maintenance dose schedule
LD = Cp x Vd
*have potential to create bolus effect
ex erythromycin is an antibacterial agent with a half life of 6 hrs. the prescribed dosage regimen is 500 mg every 6 hrs. how long will it take to reach steady state using this regimen?
what is the fold-fluctuation in Cp between doses?
T 1/2 = 6 hrs
4 or 5 x 6 hrs = 24-30 hrs
fluctuation between doses:
2^x, where x = number of half lives in the dosing interval
2^1, so 2 fold
ex if the dosage regimen for erythromycin is changed from 500 to 1000 mg every 12 hours, one will observe that:
what will the new fold-fluctuations be?
MD 500 mg
tau 6 hrs
MD 1000 mg
tau 12 hrs
fluctuations in Cp will be increased (2^1 vs 2^2)
fold-fluctuations:
2^2 or 4-fold
effect of dosing interval on Cp ss fluctuation
more half lives (NOT more hours) in a dosage interval means greater fluctuation
amount of fluctuation in Cp that can be tolerated for any drug is determined by its “therapeutic index”
Fluctuations in Cp can be blunted by slowing absorption via controlled-extended release preps
ex which drug dosage regimen would result in least amount of fluctuation in the Cp drug level during the dosing interval?
lowest ratio of tau: half life
ex. drug t1/2= 12 hrs dosed every 6 hrs
2^ 1/2
agonist
stereoisomer
antagonist
agonist- l-isoproterenol
full activity
mimic- same manner as endogenous ligands
(ex NTs and hormones)
stereoisomer- d-isoproterenol
less activity
antagonist- propanolol
no activity
block- unable to generate characteristic response
**an antagonist has NO effect in the absence of the agonist for the receptor
-extent of effect of antagonist depends on level of “normal tone” mediated by agonists in that tissue
dose response curves
increasing doses of drug and measuring the specified response to each dose
-resulting curve is hyperbola
curve is relatively linear at low doses (therapeutic range)- response usually increases in direct proportion to dose
curve levels off at high drug doses- limit to the increase in response that can be achieved by increasing the drug dose
-at high enough dose, all receptors are occupied and no further increase in response can be obtained
ED50
potency
concentration EC50 or dose ED50 required to produce 50% of the individual drug Emax
depends on:
affinity Kd of receptors for binding the drug
determines: dose to produce a given effect
- more potent the drug, the less needed for a given effect
- EC50 values used to compare potencies of different drugs
Emax
efficacy
maximal effect or power or maximal efficacy
limit of dose-response relationship on response
indicates relationship between receptor binding and ability to initiate response
efficacy most important determinant of clinical utility
potency simply determines what dose will achieve the desired level of response
ex from this equation E/Emax = D / (ED50 + D), ED50 best tells you
eqn in general shows you:
the potency of the drug
there is a limit to the increases in response that can be achieved by increasing the dose
full vs partial agonists
full- occupy receptor and produce full or max response
partial- occupy same receptor but produce less than max response
-less efficacious, 100% receptor occupancy, so decreased response
potency and efficacy can vary independently
agonists and dose response curve
x axis- log drug dose
- displays potency (ED50)
- smaller dose = more potent
y-axis- response
- displays Efficacy (Emax)
- bigger response = more efficacious
ex if 30 mg of detorolac produces the same analgesic response as 200 mg of ibuprofen, which is true?
ketorolac is more potent than ibuprofen
ex in the presence of buprenorphine, a higher concentration of morphine is required to elicit full pain relief. Buprenorphine by itself has a smaller analgesic effect than does morphine, even when given at the highest dose. Which of the following is correct regarding these medications?
morphine is a full agonist and buprenorphine is a partial agonist
morphine is more efficacious than buprenorphine
ex In the presence of naloxone, a higher concentration of morphine is required to elicit full pain relief. Naloxone by itself has no effect. Which of the following is correct regarding these agents?
naloxone is a competitive antagonist
classification of antagonists
blocks SAME receptor:
Active site (always competitive)
or
noncompetitive (active site or allosteric site)
Non receptor antagonists:
- chem antagonist- no receptor involved
- physiological antagonist- acts on different receptor
pharmacologic competitive antagonists
binds same receptor
does not elicit response
prevents agonist response
reversible nature; allows block to be overcome by agonist conc (surmountable)
EC50 increases (potency decreases) Emax unchanged --shift curve to right
noncompetitive antagonists-
- irreversible (or reversible?)
- antagonism cannot be surmounted by increasing agonist conc; func receptors have been “removed” from the sys; less receptors to contribute to the response regardless of agonist conc
EC50 minimally affected
Emax reduced
–shifts curve down
ex a reversible competitive antagonist
causes the EC50 of an agonist to increase
ex an irreversible competitive antagonist
irreversible competitive AKA non-competitive
has no effect on the potency of an agonist
causes the Emax of an agonist to decrease
physiologic antagonist
activates or blocks a distinct receptor that mediates a physiologic response opposite to agonist
chemical antagonists
does NOT involve receptor binding
acts via modification or sequestration of agonist
ex Symptoms of allergic rhinitis include nasal congestion (vasodilation) and runny nose (edema) caused by histamine’s interaction with H1 receptors on vascular smooth muscle. Loratadine is a treatment of choice, working via a competitive blockade of histamine H1 receptors on blood vessels. The role of loratadine in the treatment of allergic rhinitis is best described as:
pharmacologic antagonism
maintaining Cp in therapeutic window achieved by:
proper design of dosing regimen
quantal dose response curve
dose vs % individuals responding
plot of data provides population response
such curves can provide info on drug safety by comparing therapeutic responses to toxic responses (historically death)
ex regarding measures of drug toxicity:
quantal dose-response curves can provide info on relative drug potency
adverse reactions- extension effects side effects idiosyncratic reactions drug allergy
extension- arise from therapeutic effect; dose related and predictable (mechanism based)
side- unrelated to therapeutic goal; predictable, dose-dependent
- same drug-target interaction different organ or sys
- unrelated pharmacodynamically to therapeutic action
idiosyncratic reactions-
genetically determined abnormal response to drug; unpredictable
drug allergy- immunologic; unpredictable; dose independent
pharmacokinetic drug drug interactions can result in:
elevated drug conc’s- leading to toxicity
-via reduced elimination rates (most common) or protein-bound drug displacement (rare)
or
decrease in Cp- sub therapeutic levels
-via more rapid drug elimination (common) or decreased drug absorption
occur when 2nd drug changes Cp of 1st drug
-if still in therapeutic range- not clinically significant
patient categories at high risk for interactions:
elderly
patients in high risk clinical situations:
-dependent on drug treatment
-acute illness
-unstable disease
patients with renal/hepatic disease
patients with multiple prescribing physicians
pharmacokinetic interactions absorption ex
tetracycline plus antacids-milk
rate in = rate out
drug dose / freq = Cp x CL
tetracycline / (lower abs from antacid/milk) = (lower Cp for tetracycline so unresolved infection) x unchanged CL
pharmacokinetic interactions absorption ex
alcohol plus food
rate in = rate out
alcohol / (reduced abs speed from food) = (reduced peak Cp from alcohol, so delay and reduction in inebriation) x unchanged CL
pharmacokinetic interactions- distribution
blood flow-
drug indued decrease in cardiac output, so decreased hepatic blood flow so dec hepatic CL so incr Cp
protein binding- displacement drug drug interactions
-displacement of 1st drug from protein by 2nd drug results in increased levels of unbound-free 1st drug
pharmacokinetic interactions- metabolism
Well-documented, qualitatively and clinically most significant
Involve changes in metabolic elimination rate, can be:
Increased by inducers, leads to reduced and possibly subtherapeutic Cp levels
Decreased by inhibitors leads to increased possibly toxic Cp levels
Most interactions occur via effects on CYP450 enzymes
pharmacokinetic interactions- excretion and kidney opportunities
renal excretion- glomerular filtration (f[GFR]) tubular secretion (fixed capacity) tubular resorption (pH effect) back to blood
circumvent or prevent drug-drug interactions
modification of dosing schedules to compensate for anticipated DDI
selection of alt non-interacting drug in same therapeutic class
document all patient drug use
vigilance with narrow TI drugs
caution in high risk clinical sit’s
consider DDI if clinic course unexpectedly deteriorates
single most important determinant of poisoning outcomes
provision of good supportive care
toxicokinetic strategies
prevent- decrease toxin abs; decrease rate in
inhibit toxication- prevent toxic conversion
enhancement of metabolism- detox of toxic species
increase elimination- increase rate out
antidotes-
antagonism of toxin action at target; limited utility-
300,000 potential poisons but only 20-30 specific antidotes
ex for majority of poisoning cases, the mainstay of treatment will be:
support of vital function
prevention of absorption methods
emesis: empties stomach contents rapidly (syrup of Ipecac)
gastric lavage- wash stomach w/ saline; removal via NG tube
chemical absorption- activated charcoal (binds drug; limits abs)
osmotic cathartics- Mg Citrate or Sulfate
ex which poisoning interventions acts primarily via increasing the elimination of the toxin?
alkalinization of the urine with sodium bicarbonate
administration of a heavy metal ion chelator
enhance elimination methods
inhibition of toxication- methanol and ethylene glycol (minimally toxic until metabolized)
enhance detoxication- speed up metabolism (acetaminophen)
–acetaminophen overdose- saturates Phase 2 pathways; leads to liver damage
====treat with N-acetylcysteine
hemodialysis
manipulate urine pH
ex A homeless middle-aged male patient His breath smells like formaldehyde and he is acidotic. Which of the following is the most likely cause of this patient’s intoxicated state?
how do you treat this?
methanol; leads to formaldehyde and formic acid production; leads to severe acidosis and retinal damage
(vs ethylene glycol- oxalic acid; nephrotoxicity)
treat- with ethanol or fomepizole
ex which poisoning intervention acts via inhibiting toxication?
ethanol
and
fomepizole
ex identify the enzyme responsible for producing the hepatic metabolite of acetaminophen
CYP2E1
FDA’s role in drug regulation
- placement in Rx vs OTC categories
- evaluation process for determining safety and efficacy of new drugs
- removal of dietary supplements deemed unsafe
- equivalency of brand name vs generic drug products
4 categories of drugs
prescription (eval; prescript; low abuse pot)
controlled sub (eval; prescript; abuse pot)
OTC (eval; no abuse pot) dietary supplements (not eval)
dietary supplement
4 categories distinguished by:
evaluation of drug efficacy and safety
availability by prescription or OTC purchase
potential for abuse leading to dependence
drug vs dietary supplement
drug: therapeutic agent intended to diagnose, treat, cure, or prevent a disease
- known molec entities
- manufacturers must demonstrate proof of efficacy and safety before marketing
dietary supplement- product intended to supplement the diet; not represented as food
- incl vitamins, minerals, AA’s, herbs
- DSHEA Act of 1994- allows sale to public without prior evidence of safety or efficacy
health claims on label must contain:“This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease”.
evaluation of drug efficacy and safety
drug dev and approval process- in vitro studies animal testing clinical testing -Phase 1 is it safe (20-100 patients) -Phase 2 does it work (100-300) -Phase 3 does it work double blind (1000-3000) New Drug Application around year 8-9 marketing; patent expires 20 yrs after NDA
ex true statements regarding regulation of pharmacologically active chemicals in the US
extensive testing on animals must be performed before being tested in humans
FDA equivalency category for generic drugs
formulation has pharmaceutical equivalence
molecs have bioequivalence
effect has therapeutic equivalence
(expensive and time consuming- not required by FDA for generic drugs)
-assumed that bioequivalent drugs will be therapeutically equivalent
pharmaceutical alternatives
same therapeutic moiety
different salts, esters, or complexes of that moiety
different dosage forms (capsules vs tablets) or strengths (200 vs 250 mg)
immediate release products not equivalent to extended-release products with same active ingredient
1994 Dietary Supplement Health and Education Act
drug vs supplement classified based on intended use
if sold in US prior to 1994- not required to be reviewed by FDA for safety; presumed to be safe
-post 94- manufacturers must provide “reasonable” evidence that the produce is safe for humans (not safe and effective; but aren’t permitted to market unsafe or ineffective products; burden of proof on FDA before it’s removed from market)
bottom line- FDA has minimal regulatory control over sale and distribution of dietary supplements
supplement- vitamin, minerals, AAs, herbal meds
first 3: know molec entity imparting activity; safe dosage ranges
-info not known for majority of herbal substances
claims for dietary supplements
health
structure/function
health claim- describes effect substance has on reducing risk or preventing disease
- requires FDA authorization
- ex Ca may reduce risk of osteoporosis
structure/func claim- describes role of substance intended to maintain the structure/function of body
- no requirement from FDA
- cannot mention specific disease
- must include the infamous disclaimer on label
- ex Ca may help maintain bone health
Controlled substances
5 schedules
DEA oversees manufacturing/distribution
requires DEA number
5 schedules based on:
medical usefulness
abuse potential
potenial for dependence
1- may not be prescribed
2-4 (CO =2-5) require a prescription
2’s must be in handwriting; NO refills
3,4(5)- may be telephoned; refills ok (5x/6mo)
