Pharmacology-Unit 1 Flashcards
pharmacology
study of drug interactions (chemical substances) with biological systems
pharmacotherapy
selection of right drug/dose to interact with right target to produce a therapeutic effect
what are the therapeutic effects of pharmacotherapy?
prevention, diagnosis, treatment, cure of a disease
pharmacokinetic and pharmacodynamic principles allow what determination?
relationship btw. Dose of drug, plasma concentration (Cp) and clinical effect from that Cp
drug effects are directly correlated for what in clinical use?
Cp (plasma concentration)
graphs of what determine pharmacokinetics?
Cp vs. time
what is the MEC?
minimum effective concnentration
what can MEC be determined for?
for the therapeutic/desired response and adverse responses
onset of effect
time to reach MEC
duration of action
time above MEC
therapeutic window
difference in Cp btw. Desired and adverse response MEC
what is the goal of pharmacotherapy?
multiple doses are administered to maintain plasma concentrations at steady state in therapeutic window to produce responses with minimum toxicity
steady state
contition where rate in=rate out (elimination)
time to steady state
attained in 4-5 half lives when using maintenance doses at constant intervals
steady sate concentration
average Cp after SS is achieved
fluctuations in steady state Cp
the related number of half lives in dosing intervals (time btw. Doses)
dosage regimens are designed to ensure what?
steady state drug level is maintained in the therapeutic window
how do dosage regimens maintain a therapeutic window?
by balancing rate of elimination with prescribed rate of administration
how do you select drug and dose?
by looking at: pharmacodynamics–disease targets–drug regulation
how do you select a route of administration?
look at pharmacokinetics: absorbtion–distribution
how do you select drug duration?
base on disease pathophysiology
how do you select dosage frequency?
look at pharmacokinetics: metabolism–excretion
What should you see on a prescription?
drug, dosage, frequency, route, duration
pharmacodynamics is what?
what the drug does to the body, the mechanism of action
what does pharmocodynamics allow you to identify?
drug target and the therapeutic category of the specific drug
what are common drug targets?
intracellular receptors, enzymes, membrane transport proteins
do drugs have unique actions in the body?
NO! They enhance/blodk normal physiology of the organ systems
pharmacokinetics is what?
what the body does to the drug
what does pharmacokinetics provide a physician with?
information on absorption, distribution, elimination of drugs needed for dosing regimens
bioavailibilty (F)
how much of the dose of the drug reaches it’s target
time to peak effect (Tmax or Cmax)
how fast does the drug reach its target
volume of distribution (Vd)
what dose (mg) is needed to obtain desired Cp
absorption
passage of drug from administration site to blood
distribution
movement of drug from bloodstream to tissues
what must be considered when looking at distribution?
drug protein binding, passage across BBB/placenta, selecticve accumulation affecting efficacy/toxicity
route of administration
site of application of drug into/on the patient
what is a systemic effect?
absorbed into bloodstream for distribution ot sites of action in body
what is a topical effect?
remain at the site of application for local action
what is half life? (t1/2)
how long a drug stays at its target (duration of action)
what is elimination?
elimination of drug activity following administration. Can be done via metabolic or excratory paths
CL
clearance
describe a path of elimination/excretion
drug is absorbed into bloodstream, is distributed to site of action and organs of elimination (liver-metabolism, kidney-excretion)
what is the rate of elimination?
the length of time the drug remains in the bloodstream to exert clinical effects
therapeutic uses derive from?
mechanism of action–>Drug Target
how do drugs act?
via enhancement or blockade of physiological paths to alter an abnormal pahtophysiological disease state
are adverse reactions predictable from drug target mechanisms?
YES! Via mechanism of action
adverse reactions at a non-target system
side effects are seen at therapeutic doses, are dose-dependent and predictable
adverse reactions at target system
extension effects seen at higher than therapeutic doses (dose dependent and predictable)
adverse reactions not at drug target
idiosyncratic reactions (peculiar to individual). Less predictable/common
immunoligic reaction
allergic reaction
metabolic reaction
in origin (hepatotoxicity or blood dyscrasias)
what should you know about specific drugs/categories?
most common and severe effects
physiology of absorbtion
pharmacokinetic processes involving passage of drugs across membranes
what influences drug membrane passage?
molecular size, lipid solubility, degree ionization, concentration gradient
molecular size
can be affected by drug binding to plasma proteins
lipid solubility
estimated by oil:water partition coefficient
degree ionization
affected tissue pH, influences lipid solubility
concentration gradient
created at site of administration
list the mechanisms of membrane passage
passive diffusion, carrier mediated diffusion, endocytosis/exocytosis
passsive diffusion is driven by what?
driven by concentration gradient
aqueous diffusion/filtration
limited capacity, size varies, drugs
lipid diffusion
favored for drugs w/ high lipid:water partition coefficient, pH dependent, unionized moiety crsossed down conc. gradient. Drugs 500-800mw
carrier mediated diffusion
specialized transporters regulating entry/exit. Some transport foreign chemicals including drugs
endo and exo cytosis
vesicles that bring things in (vit B12 and iron) or release (neurotransmitters)
what does the effect of a drug on Cp depend on?
rate (time from peak to peak) and extent (bioavailability) of transfer of drug from administration site to blood
what is bioavailability (extend of absorption, F, f[%])?
the fraction of unchanged drug reaching systemic circulation after administration
how is bioavailability determined?
compare area under curve (AUC, from Cp vs. time) folloiwng a single dose of drug between IV and oral routes
what information is readily available for most drugs on extent of absorption?
bioavailability of oral route
what does knowledge of bioavailablity of a drug allow for?
dosage adjusmtents when giving the drug by a different route
IV administration
fraction of dose reading general circulation (F)=100%
oral administration
F varies from 100-0%
what does oral administration F depend on?
survival of GI environment, ability to cross GI membrane (lipid solubility, size, ionization state), efficiency of drug in gut wall/liver, variation btw. Patients
what is first pass effect?
a drug’s metabolic efficeincy in the gut wall/liver
what are some other routes of drug administration?
systemic drug action via IM, SC, inhalation, sublingual
what is the F for other routes of drug administration?
~100% (75-100%) since tissue is non-destructive to drugs
what is the rate of absorption estimated as?
the peak Cp or time to attain peak Cp plasma levels
what is the rate of absorption for oral route?
affected by preparation (liquid or rapid disentigration=faster; enteric coas or sustained release=slower), this changes time and Cp max
what is the rate of absorption for parenteral routes?
determined by the route rather than drug charachteristics. Intravenous=inhalation>intramuscular>subQ>oral
how is equivalency of drug products for the oral route determined?
FDA requires that formulations are bioequivalent. Rate and extent of active ingredient must be similar (within set limits) to brand name. if there is a 90% conficence interval in man AUC and mean Cmax is w/in 80-125% of brand name
what general factors affect drug absorption?
solubility in bilogic fluids (aq environment)=must be hydro and lipo phylic to cross membranes/distribute self; rate of solid dissoution; concentration of drug at site of administration; circulation at site of absorption; area of absorbing surface
what are the most important variable to consider about routes of drug administration?
bioavailability and rate of onset
what is the most common route for systemic effects?
oral. Slow onset of action, variable bioavailability
is absorption greater in the stomach or small intestine?
small intestine due to surface area
when is a drug favorable for absorption in GI tract?
when it is non-ionized and lipophilic
how does gastric emptying time effect absorption?
increased motility increases emptying speed and increases speed of absorption. Food delays gastric emptying and absorption
what do enteric coatings do?
prevent GI irritation, destruction from gastric secretions until they reach the basic intestines
slow release preparations do what?
slow rate of dissolution allowing for 8 hr or longer uniform absorption
what are the advantages to slow release preparations?
decreased frequency of administration, compliance, effect is maintained, eleiminates peaks/troughs
what are the disadvantages to slow release preparations?
greater independent variability, dose dumping, toxicity
describe rectal route charachteristics
not rapid onset, variable bioavailability (greater than oral route). Used when vomiting, unconscious, post GI surgery, GI irritation, uncooperative pt. 50% bypasses liver (less 1st pass than oral), faster onset of action. Useful for lipid soluble and potent drugs (
describe systemic IV route charachteristics
direct route, fastest (
describe systemic intramuscular route charachteristics
close to IV route (~90%), aqueous are absorbed quickly (5-10min), affected by blood flow/activity factors, depot/oil suspended vehicles are slower and sustained, can have erratic/incomplete absorption, can cause pain/necrosis/contamination
describe systemic subcutaneous route charachteristics
close to IV route (~100%), slower/constant rate of absorption, rate can be altered (eg: insulin), local anasthetics/contraceptives, non-irritating and volume limited
describe systemic inhalation route charachteristics
fast (
describe systemic transdermal route charachteristics
patch to skin allows for 1st pass avoidance, allows for prolonged drug levels, must be potent drug (
describe local inhalation route charachteristics
aerosol/microparticles molecules in suspension, increases local topical effects reducing systemic effects (asthma), depends on size (
describe local topical route charachteristics
treats local conditions, skin/mucosal membranes, minimal systemic absorption
how do tight junctions affect drug distribution?
tissues with tight junctions (GI mucosa, BBB, placenta, renal tubules) require drugs to pass through lipid membranes, and into/out of the blood. Drugs that can’t pass through membranes (large, protein bound, charged, hydrophilic) can’t move btw. compartments
GI mucosa absorption
oral-negligable absorption
bbb/placenta absorption
limited distribution
renal tubule absorption
filtration at glomerulus, then reduced reabsorption of drug into blood, excretion via urine
how does pH affect drug distribution?
affects lipid solubility. HH equation and tissue pH and pKa let you predict conditions favoring passage or preventing passage.
describe what dissociation of a proton does to a weak acid or base drug?
dissociation of proton from acid=ionized drug, dissociation of proton from base=unionized drug
what is the significance of ionization for drug absorption?
nonionized forms are more readily absorbed, ionized don’t cross lipid membrane
state the conditions that form nonionized acids and bases
acids become nonionized in acid medium, bases in alkaline medium
what does the HH equation allow you to predict with drugs?
the pH at which the majority of the drug will be non-ionized
what is the rule of thumb for qualitative preditions regarding drug absorption?
note whether the drug is weak acid/base, and pH of the fluid it’s in relative to pKa of the drug. pH is lower than pKA, more protons, protonated base/acid will dominate. When pH is higher than pKa of drug fewer protons, unprotonated form of weak acid/base, absorption favored.
state HH weak acid equation
HA H+ + A- [non-ionized in acidic solutions, ph
state HH weak base equation
BH+ H+ + B- [non-ionized in basic solutions, ph>pKa]
what is ion trapping?
lipid barriers separate 2 aqueous phases at different pHs, only non-ionized drugs can cross, equilibration is same on both sides of membrane, on each side of membrane separate equilibriums occur btw. Ionized and un-ionized forms of drug. At equilibrium, unionized conc. of drug is same, but total concentrationo of drug is greater on side where ionization is greater. drugs are trapped where they ionize
where are acidic drugs trapped
basic solutions
where are basic drugs trapped
acidic solutions
what is the clinical significance of ion trapping?
alters urine pH to trap weak acids/bases and hasten excretion, potential to concentrate basic drugs, weak bases are concentrated in acidic stomach contents
can ionized drug molecules cross capilary walls?
YES! Through pores.
can lipid solubility affect the rate of passage of non-ionized drugs?
YES! 2 drugs may have similar pKa, but will absorb differently
how does protein binding affect drug absorption?
will influence distribution if the free drug is diffusible. Acidic drugs bind albumin, basic to alpha-1-glycoprotein. Reduces concentration of active drug, hinders metabolic degredation/excretion, prolongs drug action, decreases volume o distribution, decreases ability to enter CNS across BBB
displacement drug interactions
displacement of a 1st drug from a protein binding site by a second drug, results in increased levels of unbound 1st drug. Total levels of drugs are unchanged b/c administration rate is the same
when does drug displacement have clinical consequences?
drug has narrow therapeutic index, started in high doses, Vd is small, response occurs more rapidly than distribution
why do most drugs act as if they display single compartment kinetics?
they are absorbed into/eliminated from a central compartment and are rapidly distributed. Some drugs may go from a second compartment (tissue) and are slower (2 compartment kinetics)
Vd
size of compartment necessary to account for total amount of drug in body if it were present throughout body at same concentration found in plasma. Gives indication of extent a drug passes from plasma to extravascular tissue. Partition coefficient btw plasma and body.
determination of Vd
single dose of drug is administered in IV (Ab), plasma concentration at time 0 (C0) is determined and Vd is calculated. Ab/C0
distribution compartments
distribution may not be homogenous. Sites are speculative w/o comparison
what are the volumes of body compartments?
plasma=3-5L, extracellular water=12-15L, total body water=42L, other compartments >50L
higher values of Vd indicate what?
drugs are located outside the plasma (lipid soluble, tissue binding)
lower values of Vd indicate what?
drugs located inside plasma or ECF (bind plasma proteins, large size, low lipid solubility)
what are the values of Vd?
L/kg
Vd allows you to determine what of a dose?
effect a dose will have on Cp. Dilution factor. Cp=D/Vd
necessary dose calculation
LD=Cp desired x Vd. The loading dose (LD) to fill the distribution volume to achieve steady state plasma
what is biotransformation/drug metabolism?
enzyme catalyzed chemical structure transformation
what are the general principles/charachteristics of drug metabolism?
enzymes have endogenous substrates and play role in metabolism, liver is the primary organ of metabolism (others can do it too), oxidation is the most frequent path (some by enzyme bound of smooth ER, some by cytosol enzymes), lipid soluble compounds are converted to water soluble then excreted
biotransformation phase 1
inserts/unmasks fundtional group into drug rendering it water soluble and able to be conjugated. Oxidation, reduction, hydrolysis
biotransformations phase 2
conjugation. Combine with pre-existing/metabolically inserted functional groups, forms polar conjugate excreted in urine.
what type of process is drug metabolism?
detoxifying. Forms readily excreted metabolytes (inactive). Drug metabolized to less active compound
what are other metabolic outcomes?
can become more active drug, inactive to active, toxic metabolyte
what are cytochrome p450-dependent oxidations?
part of oxidation system that includes NADPH, NADPH-cytochrome P450 reductase, molecular O2. Liver is richest source
list the charachteristics of CYP450
substrate must be lipid soluble, inducible, inhibitable, postnatal development variable, different isozymes
inducibility
increase in enzyme protein and drug metabolizing activity
postnatal development variable
early neonatal levels exist at 50-75% of adult, some are metabolized faster
isozymes of CYP450
CYP1-3
how are pateints classified regarding enzyme activity?
ultra rapid metabolizers (UM) or decreased/poor metabolizers (PM). Depends on ethnic groups.
amplichip cyp450 test
analyzes blood derived DNA and detects genetic polymorphisms in activity of CYP2 D6 and C19. these account for 25% of drug metabolism
what does clinical effect depend on?
whether metabolism is detoxifying or activating and whether polymorphism results in increase or decreased enzyme activity
PM CYP2D6 detoxifying
increased antipsychotic drug toxicity
UM CYP2D6 detoxifying
nonresponse to antidepressants
PM CYP2C19 activating
decreased PPI efficacy for peptic ulcer disease
PM CYP2D6 activating
insufficient analgesia with codine-dont metabolize to morphine
UM CYP2D6 activating
codeine intoxication-too rapid metabolism
differences in warfarin response may be due to genetic variation in?
vitamin K reductase (what it targets), CYP2C9 (metabolizes)
cytochrome P450-independent oxidations
several types, dehydroginases, oxidases
amine oxidases
located in outer membrane of mitochondria (monoamine oxidase), important for neurotransmitter metabolism
dehydrogenations
alcohol dehydrogenase, hepatic soluble fraction, several types, reached at 5 yr, aldehyde dehydrogenase
list the reductions of Phase 1
azo reduction (activates slfonamides), nitro reduction (diff. enzymes; toxic intermediate), carbonyl reduction
list hydrolysis of phase 1
esterases, amidases
esterases
adult values in 1st few months (used for pro-drugs). Hydrolyze exters to alcohol and acid, very reactive. Present plasma, liver, tissue.
amidases
liver and gut, amides to acids and amines
conjugations of phase 2
synthetic transformations. Drug or drug metabolite is condjugated to endogenous biochemical unit by a coenzyme. Done by transferases. Product is often water soluble and excreted.
glucuronidation
create conjugates that are excreted in urine, some in bile, some in feces. Groups that conjugate: aliphatic OH, aromatic OH, COOH, NH, SH. When doen by beta glucuronidase results in free drug
gucuronyl transferases
microsomal enzymes in liver, kidney, GI. Inducible.
enterohepatic recirculation
drug secreted by liver into bile as conjugate then absorbed by GI as free drug. Source of drug interactions?
n acetylation
amide bond formation via n-acetyltransferase. Donated by acetyl CoA. Catalyzed in hepatic soluble fraction. Products can be less water soluble
glutathione conjugation
glutathione s-transferases have limited role in drug metabolism. Detoxify carcinogens, pollutants, toxic metabolites
sulfate conjugation
forms strong acids (pKa ~1). Sulfotransferases occur in soluble cell fraction. Ionized and water soluble conjugates. PAPS is coenzyme. Acceptors: aromatic OH, N-OH
what is induction?
stimulation of CYP450 system resluting in increase drug metabolizing activity. Observed in >300 compounds
what is the mechanism of induction?
increased synthesis of enzyme protein. Accompanied (sometimes) by morphological/biological changes (liver weight increase, proliferation SER, NADPH and CYP-450 increase). Requires 48-72 hrs for effect
list mechanisms of inhibition
inhibit enzyme synthesis, compete with substrate, inhibit without being a substrate, metabolite formation (suicide inhibition or tight complex)
how do most interactions occur on Cytochrome P450 system?
effects are obvious through oral routes: pass through liver, inducers increase metabolic rate, decreasers decrease amount of drug available for interaction
what are therapeutic consequences of induction?
maximal effects of enzyme induction, production of pharmacokinetic tolerance, induction (increase other drug clearance, implications=reduced therapeutic effect/increased toxicity), induce metabolism of another drug to toxic metabolites
what are therapeutic consequences of inhibition?
can occur when sufficient hepatic concentration is reached, inhibition by one agent can result in decreased clearnce of inhibited drug (higher Cp/toxicity)
what are some biological factors that influence drug metabolism?
diet and nutrition (high protein stimulates mixed function oxidase), malnutrition (changes drug metabolism), sex differences, age (perinatal vs neonatal vs old age)
what are some genetic factors that influence drug metabolism?
metabolism mediated by enzymes is genetically controlled. See notes for more depth
What are some disease states consequences that influence drug metabolism?
require dosage adjustment/avoidance. Hepatic diseases (effect depends on severity, drug, biotransformation), alcohol consumption (inhibits transformations, chronic exposure-induction microsomal biotransformations, cirrhosis), blood flow to liver issues reduce rate of elimination, non-hepatic diseases reduce drug metabolism.
transportors on membranes of intestinal, renal, hepatic epithelial cells play a role in eliminating what?
xenobiotics (including drugs). Most important is P-glycoproteins (MDR1 gene) (ABC=Atp Binding Cassette, pumps fueled by ATP)
where are ABC transporters located?
renal brush border membranes, bile canaliculi, astrycyte foot processes (brain), GI tract
what do ABC transporters do?
move molecules out of cell at sites of entry into body. Also decrease absorption at sites of exit (enhance elimination)
how many genes code for polymorphic variations and transporters that contribute to individual genetic variation in drug response?
over 300
inhibitors of p-glycoproteins will ______ plasma levels of drug substrates
increase
inducers of p-glycoproteins will ______ plasma levels of drug substrates
decrease
what organ is the most important for drug excretion?
kidney. For water soluble/non-volatile compounds
glomerular filtration clears at a rate of ? mL/min
120
drugs smaller than _____ are filtered by kidney
albumin (MW 69,000)
is protein bound drug filtered?
NO! only free drug
what 2 thing affect renal excretion?
renal blood flow and renal function
what is the half life of drugs cleared by the kidney?
t1/2~1-4 hrs (lots of protein is a longer t1/2)
active tubular secretions are drugs transported from ____ to ______
blood to urine
how quickly can actively secreted drugs be cleared?
120-600 mL/min
where does active tubular secretion occur and with what types of drugs?
proximal tubule with stronger acids and bases
what are some acid and base substrates for tubular secretion?
acids (penicillins, diuretics), bases (morphine, catecholamines, histamine, tolazoline)
does plasma protein binding affect rate of secretion?
not appreciably (T1/2~1-2 hrs)
how quickly are drugs that are lipid soluble and uncharged cleared?
at the rate of urine formation- 1mL/min
a primary function of drug metabolism is to produce _____ that is less likely to be reabsorbed.
water soluble metabolite
where does passive diffusion occur in the kidney?
in proximal and distal tubules with lipid soluble molecules
diffusion of weak acids/bases in distal/proximal tubules depends on ______.
urine pH. Non-ionized form will diffuse across membrane
what changes urinary pH to acidify or alkalize it?
NH4Cl/ascorbic acid acidifies, NaHCO3 alkalinizes
active reabsorption is important for ______ compounds
endogenous (glucose, AA). Drugs act to reduce this active transport
many drugs (high molecular weight) are excreted into _______, then _______ by small intestine where they can be ______ in the urine
the bile, resorbed, eliminated
drug metabolites (as conjugates) are ____ into the bile where they are ______ by bacterial enzymes back to ______ (more lipid soluble) and are _____ by the gut (enterohepatic recycling)
secreted, hydrolized, parent, resorbed
enterohepatic cycle
drugs and metabolites w/ molecular weights >300 are excreted via bile, stored in gallbladder, delivered to intestines, resorbed to circulation where can go to liver. Reduces drug elimination, prolongs half life/duration
how much of a reservoir can a recirculating drug have in the body?
20% of the total drug present
antibiotics decrease _______ recycling and _______drug levels
enterohepatic, plasma. They are a potential mechanism for drug-drug interactions
do drugs cross into breast milk?
yes, but at low levels. Infant plasma level is below therapeutic level. Can work to reduce possible reactions. Breast milk is more acidic than plasma-can ion trap.
what drugs can affect milk synthesis?
dopanimne receptor agonists/antagonists and ethanol
drug assays can be performed on samples from what 3 things?
sweat, saliva, hair
first order kinetics
principle that governs rate of drug elimination. How almost all drugs are eliminated
rate of elimination (mg/hr) is ______ to concentration of drug in _______.
proportionsl, plasma (mg/L)
how is the relationsip of the rate of elimination complicated?
as drug is eliminated, concentration changes, so rate of elimination changes constantly
when are most drugs eliminated by first order kinetics?
when they are given in does w/in the therapeutic dosage range
what major biologic processes are first order processes responsible for drug elimination?
hepatic metabolism and renal excretion
Cp vs. time graph
slope represents rate of elimination (mg/ml per time). Steep when Cp is high, slows as drug is eliminated
lof of Cp vs time graph
follows a straightl ine
the ________ rate of elimination changes constantly along with amount of drug eliminated in first order kinetics
absolute
a ______ fraction of drug is eliminated per unit time in first order kinetic elimination.
constant (independent of total amount of drug present)
half life (t1/2, units of hours/minutes) in 1st order kinetics
the time required to eliminate 1/2 of the drug present
how long would it take a drug with a t1/2 of 3 hours to decline from 1000 to 500 mg/mL?
3 hours. Duh.
how long does it take plasma concentration to decline from 500 to 250 mL?
3 hours
rules of thumbs for estimating t1/2 calculations
time for elimination from plasma=4-5 half-lives; time to reach steady state plasma drug levels after multiple doses=4-5 half lives; fluctuations in plasma levels between doses=number of half lives in dosing interval
when t=t1/2 then C2=????
1/2 C1
what is ke?
the fraction of drug leaving body per unit time via all elimination processes
ke is best thought of as a _______ or _______ allowing us to calculate the amount of remaining drug at any time in the elimination process
number or constant
what is clearance?
the Vd which is cleared of a drug in a given period of time by combined processes of tissues (kidney, liver) with some contribution from other tissues (lung, muscle, etc.)
what formula gives us the value of clearance?
CL= Vd x Ke. This volume remins constant through course of elimination
the actual amount of drug eliminated depends on its _____ in the cleared volume at any particular time
concentration
how is clearance BEST thought of?
proportionality constant that makes Cp at steady state = to the rate of administration
clearances from each organ of elimination are ______
additive
which 2 organs are most important for clearing most drugs?
kidney, liver
clearance ranges from just above _____ to a _______ determined by blood flow to organs of elimination
zero, maximum
CL (total body) = ???
CL (renal) + CL (hepatic) + CL (all other routes)
hepatic clearance is subject to.?
co-administration of inducers and inhibitors. Varies with blood flow to liver, protein binding, intrinsic metabolic activity
if metabolism is unefficient, are changes in hepatic blood flow clearance influenced?
not significantly
if metabolism is efficient are changes in hepatic blood flow clearance influenced?
major influence on total body clearance
what 2 things are used to measure kidney function?
CrCL (creatinine clearance) or serum creatinine clearance (SCr)
changes in renal function will _________ clearance of renally eliminated drugs and ______ dose changes to prevent accumulation
alter, necessitate
a graph of ln concnetration vs. time is composed of ________ portion representing _________ phase of drug equilibrating btw blood and tissue
initial curvilinear, distribution
linear portion of graph represents the ______ phase of drug elimination
elimination
when discussing pharmacokinetics, it is assumed the route of administration is ____ and bioavailablity is ___%
IV, 100%
for a drug with oral bioavailability of 50% (F=0.5), IV dose would need to be divided by _____ to calculate necessary oral dose
0.5
if IV dose is 100 mg, what is oral dose?
100/0.5=200 mg
what happens when a drug is administered by infusion at a constant rate?
Intially, Cp rises with time, but as it rises, rate of elimination rises. The rise continues until increasing drug concentration produces rate of elimination equal to constant rate of infusion—Steady State Exists!
when is infusion stopped?
when plasma concentrations (reflecting elimination) after constant infusion reach steady state and are turned off.
after a drug is discontinued, how long does it take to be eliminated?
it is assumed it is eliminated after 4-5 half lives (ie: only 3.12-6.25% steady state remains, no effect)
time to reach steady state AND plateau is related to what?
half life of drug ONLY. This is independent of dosage.
will increasing a maintenance dose allow the steady state to be reached sooner?
No. It will cause the steady state plasma level to be higher when it is reached
How do you reach a desired steady state plasma level sooner?
administer a loading does with a normal dose schedule after
when is a loading dose given?
in clinical situations where you can’t wait for the 4-5 half lives for therapeutic levels to be reached.
what is a loading dose?
loading doses are higher than maintenance doses to help you approach steady state plasma levels more quickly
how do you calculate loading doses?
estimate using the Vd for the drug and desired Cp. LD (mg)= Cp0 (mg/L) x Vd (L)
can the calculated loading dose cause toxicity?
YES! Due to transiently high lpasma levels in the alpha-distribution phase. Can be lessened if you give the LD over a longer interval that still gets you faster than 4-5 half lives
________ lead to fluctuations in plasma drug levels (as opposed to continuous infusion).
repeated administrations (of a dose of drug)
What is useful to know when shooting for a therapeutic endpoint (Cp average at steady state)?
the amount of fluctuation btw max and min Cpss in a dosing schedule
average steady state concentration is the ______ for intermittent and continuous infusion
same
what fluctuates between doses of intermittent drug infusion?
plasma concentration. Size increases with dosage interval increase.
what is the magnitude of fluctuation equation?
1/fraction of drug remaining at end of dosing interval [Cp2/Cp1]
T1/2 is useful in _____ estimating an appropriate dosing interval (tau) for maintenance therapy.
qualitatively
if tau is
less thatn 50% in the dosing interval
if tau is larger than t1/2, how much of the drug is eliminated before the next dose?
all of the drug (effectively), fluctuation is maximal
if tau is shorter than t/12 how much fluctuation is there?
little
the more t1/2’s in a dosage interval the _________the fluctuation.
greater
how can fluctuations in plasma levels be blunted?
slow absorbtion via controlled/extened release preparations
zero order kinetics describe the rate of what from the body?
rate of elimination that is independent of the drug in the body
are zero order kinetics first order?
NO! the amount of drug removed per unit time is constant (independent of concentration)
how do zero order kinetics occur?
saturation of hepatic metabolic enzyme systems via drug administration
do drugs eliminated by zero order kinetics have half lives?
NO! This presents dosage challenges, at upper end-large changes in Cp
a drug is a.?
neurotransmitter-hormone
recognition and binding occurs at the?
receptor
signal transduction occurs via?
g-proteins or other effectors
amplification occurs via.?
transport of ions/molecules, transcription factors, enzyme activation/deactivation, protein synthesis, release of neuroactive agents
what occurs after amplification?
physiological response
list the generalized scheme of drug action.
binding of drug to receptor, transduction, transduction and amplification, physiological response
drug receptor
component of system that drug binds to and causes a change in the system function. Specificity is important
transduction
alters celular function via effector molecules. Components of system that create biologic effect after activation (translate the interaction of drug and receptor into cellular activity)
major mechanisms of transduction and amplification
ligand gated ion channels, g protein coupled receptors, kinase linked receptors, hormone receptors
physiological response examples
muscle contract/relax, neurotransmitter release, changes transcription/protein synthesis
specialized receptors
designed to detect chemical signals and initiat response through signal transduction paths
generalized receptors
molecules with any function (eg: enzymes, lipids, NA)
list some types of receptor molecules
proteins, nucleic acids, membrane lipids
are protein receptor molecules specific?
yes. Most specific
are receptor nucleic acids and mebrane lipids specific?
no. lower specificity
receptors are responsible for _________ of drug action
selectivity. Size, shape, charge determine binding affinity. Changes in chemical structure affect affenity
some drugs can bind and regulate the function of receptor macromolecules as ______.
agonists, they act in the same way as endogenous ligands-promote receptor function
drugs as pharmcologic agonists
bind receptors, cannot generate charachteristic response. Prevent binding of endogenous agonist molecules to receptor to block action
receptor theory and does-response curves
this theory allows determination of quantitative relationships btw. Dose/concentration of drug and it’s effects via the response curve.
what is necessary to know about a therapeutic drug option when choosing between different types?
potency and efficacy
explain what drug receptor theory assumes
interactions folllow mass action relationships, binding is reversible, response is proportional to receptors occupied by drug. RD is proportional to response
what shape do you want to see in a dose vs. response curve?
hyperbola. This confirms the mathematical relationship btw. Dose and response.
what does a hyperbolic shape of a dose-response curve indicate?
curve is linear at low doses, curve levels off at high drug doses (limit to the increase of response achieveable)
what does a log dose-response curve allow you to do?
It allows you to plot a wide range of doses for comparison, dose response relationship is nearly a straight line over many dose ranges. No special biologic or pharmacologic significance
potency
concentration or dose required to produce 50% of drug’s individual maximal effect
what does potency depend upon?
affinity of Kd of receptors for binding, and efficiency of the drug receptor comples to generate a response
the potency of a drug provides info on _____ drug is required to produce an effect
how much (dose)
maximal effect or efficacy
the limit of dose-response relationship on response (y axis). Relationship btw binding to the receptor nd ability to create a response at molecular, cellular, tissue, system
what is the most important determinat of a drug’s clinical utility?
it’s efficacy
potency determines what______ is needed to achieve a desired level of _______
dose, response
agonists
drug that activates receptor and brings about a tissue response
full agonists
drugs that occupy receptors to create MAXIMAL responses
partial agonists
drugs that occupy same receptor as full agonist but create a less than maximal response at even full dosage levels
are partial agonists more or less efficacious?
less
potency and efficacy vary ________.
independently. For example, partial agonists may be more, less, or equally potent than full agonists
when 2 drugs don’t produce maximal response charachteristics of the tissue, the observed maximal response is a function of their _______.
relative intrinsic efficacies.
the vast majority of agonist drugs in clinical practice are _______agonists.
full
pharmacologic potency
determines the dose needed to be administered to the patient
clinical effectiveness of a drug depens on its __________ and ability to reach the relevant receptors.
maximal efficacy
in therapeutics, efficacy refers to the extent a given ________ can be achieved in a patient.
clinical effect
antagonists
drugs that inhibit actions of agonists with no effect in absence of an agonist. Receptor and non-receptor.
receptor antagonists
bind the same receptor as agonist
nonreceptor antagonists
physiological antagonists that bind different receptor and chemical antagonists that bind agonist molecule directly
competitive reversible antagonist
antagonist binds reversibly to active site but doesn’t stabilize it to confirmation required for activation. Blocks agonist binding
Emax is _______ with competitive reversible antagonists
unchanged. Potency decreased. Curve shifts right. Maximal efficacy of agonist is unchanged because agonist concentration can be increased to outcompete antagonist
noncompetitive antagonists
binds irriversibly or pseudoirreversibly to active site or allosteric site of receptor
Emax is ______ with noncompetitive antagonists
decreased. Potency unchanged. Curve shifts downward, maximal efficacy is reduced.
what are the 2 nonreceptor agtagonists?
physiologic and chemical antagonists
physiological antagonist
activates or blocks a receptor that mediates physiologic response oppposite of activation of receptor for agonist
chemical antagonist
doesn’t bind receptor. Occurs via inactivation of agonist itself (modifies or sequesters it).
quantal dose response (effect) curves charachterize.?
pharmacologic respones in all or nothing events in a population. Generated by arbitrarily defining some specific therapeutic effect and determining minimum dose to produce the response in the population
all or nothing
brings about the response or it doesnt
benefit-risk ratio
provides a measur of how safe a drug is clinically.
therapeutic effect
benefits. All or nothing response. Intiate till response achieved
ED50
the dose that initiates effect in 50% of test population
how can the degree of risk be evaluated?
by comparing quantal dose-response curves for desirable and toxic effects
LD50
lethal dose that causes death in 50% of subjects
TD50
dose that produces undesirable effect in 50% of subjects
therapeutic index
LD50/ED50=TI. Factor by which dose is therapeutically effective in 50% of population must be increased to cause death in 50% of the population.
the _____the therapeutic index, the safer the drug
higher
what is the therapeutic index of most drugs?
greater than 10-20
standard safety margin
percent by which dose effective in 99% of the population must be increased to cause death in 1% of the population.
is the standard safety margin more or less conservative than the therapeutic index?
more. Takes into account the population extremes (rather than midrange)
therapeutic window
concept used to provide indication of safety of a drug. Thought of as the safe “opening” btw. The minimum therapeutic concentrationand minimum toxic concentration of drug in plasma and dosage regimens.
adverse reactions
response to a drug that is not desired/harmful/occurs at usual doses.
extension effects
dose related and predictable. Arise from extension of therapeutic effect
side effects
predictable, dose dependent reactions unrelated to the therapeutic goal. Produced by same receptor responsible for the therapeutic effect at a different organ/system
idiosyncratic reactions
genetically determined abnormal response to a drug, unpredictable.
drug allergy
adverse response of immunologic origin, unpredictable, severity is dose dependent
what are the 5 categories for classifying risk to a fetus with a drug?
safe (A) to teratogenicity (X). Most drugs are in B/C/D categories. See notes for full description of each
drug drug interactions
categories of patients and specific drug/drug classifications are associated with increased risk for interations. Must be aware of these!
pharmakokinetic drug interactions can result in ______ drug concentrations leading to toxicity OR they may cause _____ in plasma concentrations leading to levels below therapeutic effectiveness.
elevated, decreases
what patient categories are at high risk for drug-drug interactions?
elterly, high risk, renal/hepatic disease, multiple prescribing physicians
single most important determinant of poisoning outcomes is the provision of __________ (3 words).
good, supportive care
list the supportive measures needed in poisoning cases:
cardiopulmonary, electrolyte/acid-base balance/fluids, CNS precautions, renal function
toxicokinetics
study of absorption, distribution, eliminaton of toxic parent compounds and metabolic producs that aids in prediction of amount of toxin that reaches site of injury and damage
volume of distribution can be useful in predicting which drugs would be removed by ______.
dialysis/exchange transfusion
pharmacokinetic treatment strategies for toxic poisoning
prevent/decrease absorption (decrease rate in), inibition of toxication, enhancement of metabolism, increase toxin elimination
pharmacodynamic treatment strategies for toxic poisoning
antidotes
emesis
empties stomach contents rapidly. Ipecac, amorphine. Be careful of contraindications (comatose, corrosive poisons, seizure risk, pregnancy)
things to do to prevent absorption of poisons
emesis, gastric lavage, chemical adsorption/activated charcoal, osmotic cathartics
lavage+emesis removes ____% of poisons
30%
when is lavage best timing wise?
within 60 minutes of ingestion
what do osmotic cathartics do?
decrease time of toxin in GI tract. Sorbital is recommended (70%).
symptoms of toxicity (poison)
appearance is delayed by 8-36 hrs. severe is 4-12 hrs. methanol=visual disturbances (formic acid on optic disc). Etylene glycol=damage to kidneys due to calcium deposits
mechanism of toxicity
alcohols are well absorbed orally and metabolized to organic acids. Methanol/ethylne glycol-minimal toxicity till metabolized (formic acid). Rate limiting enzyme is alcohol dehydrogenase-inhibit with fomepizole
severe poisoning treatment
suppression of toxic metabolites, hemodialysis, correction metabolic acidosis.
acetominophen toxicity symptoms
4 stages: initial 24 hrs=nausea vomiting abdomen pain (symptoms don’t show the severity), 24-48hrs=hepatic damage apparent (plasma aminotransferases elevated and prolonged prothrombin), 72-96hrs=peak hepatotoxicity (severere hepatic necrosis), 7-8 days=recovery if timely treatment (if not timely, severe damage in 10%, 10-20% death of liver failure)
phases of acetomenophen
conjugated with glucoronic acit/sulphate (phase 2 rxn)–>phase 1 cytochrome P450 oxidation–> metabolite is detoxified by phase 2 GSH-transfease–> mercapturate excreted
hepatocellular injury involves ______ of phase 2 sulfate and glucuronide conjugation paths by toxic doses.
saturation. Results in excessive formation of Ac* by unsateruated IP450 path, depletion of cellular gluthatione, binding of NAPQI to critical protein or cellular constituents
how do you treat acetomeniphin poisoning?
gastric lavage in 4 hrs, supportive therapy, N-acetylcysteine in 12-36 hours of ingestion ( precoursor glutathione syntesis)
entracorporeal removal of toxins from blood
potential complications and expense are high. Hemodialysis/peritoneal dialysis (blood pumped through filter, effective for small Vd toxins), hemoperfusion (blood pumped through column of adsorbent material)
enhanced metabolism removal of toxins from blood
since cytochrome P450 metabolism takes 1-3 days it’s not realistic. Instead, enhance detoxification paths with N-acetylcysteine. Inhibit metabolism to block metabolites that are toxic.
is enhanced renal excretion of proved value for removing toxins from blood?
no. done with forced diuresis or blocking reabsorption from kidney
chelation of heavy metals for removing toxins from blood
combines aspects of enhancing the elimination of toxin and inactivating it.
how does normal chemistry work with heavy metal ions?
heavy metal ions form coordinate covalent bonds with protein side chain nucleophiles
how do toxic mechanisms work with heavy metal ions?
they interact with macromolecule essential to normal function, and form tight covalent bonds. Toxic manifestations are due to enzyme inhibition and alteration of membrane structure
how do you treat heavy metal toxicity?
administer chelating agents that complex with free metal ions in body fluids.
federal government controls what in relation to drugs?
what drugs can be sold to the public via the FDA
FDA regulates what in relation to drugs?
evaluation process for safety and efficacy, removal of dietary supplements deemed unsafe, equivalency to brand names, placmetn of drugs into prescription/non-prescription categories
can local governments pass laws about drug use in their jurisdiction?
Yes.
what are the distinguishing factors of the drug categories of prescription or controlled substances?
whether they are evaluated for efficacy and safety, availability by prescription for direct purchase, potential for abuse for pysiologic/psychologic dependence
drug
molecular entity as a therapeutic agent intended to diagnose, treat, cure or prevent a disease
what does the FDA require of new drugs released since 1938?
that they demonstrate proof of efficacy and safety before marketing to public
dietary supplement
defined as product intended to supplement the diet, contains vitamin, mineral, amino acid, herb/botanica. Not food. Can be sold without prior evidence safety/efficacy.
evaluation of drugs steps (list):
animal studies, clinical trials in humans, phase 2, phase 3, post marketing surveilance
phase 2 clinical trial
2 year clinical investigation. Does it work in patients? 200-300 pts
phase 3 clinical trial
fulll scale clinical trial, 3 years. Does it work double blind? 1-6000pts
abbreviated new drug application (ANDA)
submitted for generic drugs allowing manufacturer to bypass clinical trials. Bioequivalence standards must be met
phase 4 clinical trial (post marketing surveilance)
submit reports to FDA of adverse effects. FDA can revoke approval/restrict drug use.
are most generic brands bioequivalent?
yes. Bioavailability variation is less than 4%
what are the 2 drug categories where 1 formulation consistently is advised ( or use of name brand is recommended)?
levothyroxine and anti-epileptic drugs
pharmaceutical equivalents
drugs with same active ingredient in same dosage formulation, same administration route, inentical strength/concentration
pharmeceutical alternatives
products w/ same therapeutic moiety, with different salts, esters, complexes, dosage forms, strengths
extent of absorption
area under the plasma concentration time curve (AUC) and rate of absorption. Estimated by maximum of peak drug concentration Cmax
therapeutic equivalents
equivalents that when administered to the same individual in the same regimen, provide same efficacy and safety.
dietary supplement definition
supplement diet, taken by mouth, one or more dietary ingredients of vitamins/mineral/aa/botanicals or herbs
regulation of dietary supplements
classification is based on intended use
do supplement manufacturers have to provide evidence to FDA that their products are save and effective?
NO. not permitted to market unsafe/ineffective products. Minimal regulatory control of restricton/removal by FDA once marketed
do health claims require FDA evaluation?
YES! They must be authorized too.
structure/function claim
describes role of substance intended to maintain structure/function of body. Don’t require pre-approval. Must have disclaimer that not evaluated by FDA
do all ingredients have to be listed on the label?
yes
medical foods
food formulated to be consumed/administered enterally under the supervision of a physician, intended for specific dietary management of disease or condition
OTC status requirements
is the condition self-diagnosible/treatable?, what is product toxicity/habit forming/high dose safety?, do the benefits outweigh the risks?, do methods preclude OTC availability?, can directions be written and understood?
prescription
written or verbal order from prescriber to pharmacist concerning medical substances for patient
what is required on a prescription?
construction of drug product, date, identity of prescriber (preprinted), patient info, Rx symbol, drug strength, directions to patient (amount, time, frequency, route administration, duration), chart info (name, strength, dose, route, frequency, date, signature), refill info, childproof container, signature, DEA number
controlled substances act of 1970 provides for control of manufacture/distribution of drugs and divides into _____ schedules.
- based on potential for usefulness, abuse potential, degeree of which they may lead to physical/psychological dependence
schedule 1 drugs
high abuse potential, no current medical use: opioids, haluciongens, depressants
schedule 2 drugs
high abuse potential, high abuse potential: opioid analgesics, stimulants , barbituates
schedule 3 drugs
accepted medical use, moderate abuse: opioids, stimulants, depressants, anabolic steroids, cannabinoids
schedule 4 drugs
accepted medical use, low potential abuse: opioids, depressants,stimulants, benzodiazepines, hypnotic agents
schedule 5 drugs
accepted medical use, lowest abuse potential: opioids in low amounts
what drugs can be/require a prescription?
schedule 2-4 drugs (colorado is 2-5)
which prescriptions can be phoned in?
3-4. Schedule 2 drugs must be handwritten
should you use abbreviations in prescriptions?
NEVER!
