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what is a drug?
any substance that causes a change in biological function
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what is a therapeutic agent?
a drug molecule that has the purpose of correcting physiological function
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what can different doses of a drug result in?
- therapeutic effect
- side/toxic effect
- lethal effect
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effective drugs require what dose for a therapeutic effect
a lower dose
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agonist
a compound that stimulates the biological process
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antagonist
a compound that inhibits the biological proces
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most drugs mediate their effect through
receptor-drug interaction
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4 typical drug targets
- enzymes
- membrane receptors
- transporters
- ion channels
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2 things that can cause a stronger drug effect
- stronger interaction b/w drug and receptor - the better the shape fits, the higher the affinity
- higher concentration of drug > more to bind and replace immediately as one drug falls ff
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how is drug binding reversible?
b/c most interaction b/w drug & proteins are through hydrostatic bonds - which are weak and reversible
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what is a caveat of drug?
- we cannot control 3D structure when creating drugs
- diff. conformations/enantiomers = diff effects
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racemic mixture
equal amounts of left and right-handed enantiomers
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how do you separate the 2 enantionmers of a drug?
- very diff and expensive
- usually the non-effective drug's effect is so negligible that it is fine to leave it in (not effective unless giving in much higher amount)
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allosteric ligand
- affects activity (+ or -) by binding away from main site
- may induce confirmational change that changes shape of protein/its binding site
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pharmacokinetics
effect body has on the drug
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pharmacodynamics
effect of drug on the body
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steps that drug has to go through in the body
- absorption
- distribution
- metabolism
- elimination/excretion
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what determines concentration of drug at site of action?
dose
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absorption of drug depends on
route of administration
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10 routes of drug administration?
- oral
- subcutaneous
- intramuscular
- intravenous
- inhalation
- intra-nasal
- sublingual
- transdermal
- rectal
- intrathetcal
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2 main routes of drug administration?
IV and oral (PO)
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enteral vs parenteral drug administration?
- enteral - through GI tract, includes oral, sublingual, and rectal
- parenteral - inludes IV, intramuscular, subcutaneous
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advantages of enteral administration of drugs?
easy, convenient, safe, most common
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disadvantages of enteral drug administration?
- requires patient cooperation
- slow absorption - main issue
- first pass elimination - degradation of drug in stomach & liver after portal system takes drug to liver
- irritation to GI > vomiting
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what is the job of the liver?
to detoxify compounds, which ends up destroying many drugs
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solution against first pass elimination?
increase concentration of drug to get the desired effect
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which drugs should be taken on empty stomach? why?
- basic drugs
- no food = less stomach acid = faster emptying of stomach = quickly absorbed into intestine
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which drugs should be taken with food? why?
- drugs that like acidic env, weak acids
- more food = longer time for stomach to wait before emptying = mmore time for drug to spend in stomach's acidic env and get absorbed
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advantages of subcutaneous injection drug administration?
- bypass GI, directly into body, easy
- slow and sustained effect, which may be good for some drugs (ex. insulin)
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disadvantages of subcutaneous injection drug admin?
- risk of infection, needle sharing
- slow absorption - only good for drugs that prefer slower absorption
- small amounts
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advantages of intramuscular drug admin?
- bypass GI (and first pass elimination), directly into body
- faster absorption due to better circulation
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disadvantages of intramuscular drug admin?
- risk of infection, needle sharing
- small amounts
- painful
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the rate of drug absorption following intramuscular/subcutaneous injection depends on _________
rate of blood flow to injection site
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advantages of IV drug admin?
- speed - no absorption needed, directly into bloodstream
- precise control of concentration (no breakdown)
- Bypass GI + first pass elimination
- large amounts possible
- eliminates GI discomfort
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disadvantages of IV drug admin?
- cant be recalled after administration (in case of mistake)
- conc. at injection site is very high (can be toxic to vasculature of heart)
- could precipitate in blood
- greatest risk of infection
- more difficult to perform
- high risk of overdosing\
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2 main advantages of IV drug admin?
accuracy + immediacy
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advantages of inhalation of drug?
- bypass GI, directly into body
- very fast delivery into bloodstream
- much safer than injection
- very effective
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disadvantages of inhalation of drug?
only suitable for some drugs
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advantages of intranasal drug admin?
- bypass GI, directly into body
- very fast delivery into bloodstream
- much safer than injection
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disadvantages of intranasal drug admin?
only suitable for some drugs
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advantages of sublingual drug admin?
- bypass first pass elimination, directly into body
- very fast delivery to bloodstream
- much safer than injection
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disadvantages of sublingual drug admin?
- taste
- only available for some drugs (have to be hydrophobic to be absorbed this way)
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2 examples of drugs that can be administered sublingually?
- 1. nitroglycerine - for chest pain
- 2. lollipop of opioid analgesic - pain med/morphine at home for cancer pts
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why is sublingual absorption so effective?
venous drainage from mouth is to superior vena cava - avoids first pass elimination
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advantages of transdermal drug admin?
- bypass GI, directly into body
- very safe
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disadvantages of transdermal drug admin?
- only suitable for some drugs
- very slow absorption
- can be irritating
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what does transdermal drug absorption depend on?
lipid solubility
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when is rectal administration useful?
when pt is unconscious or uncooperative (baby or altered mental status)
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lower rectal veins drain directly to?
inferior vena cava
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upper rectal veins drain directly to?
portal system
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rectal admin is only good for?
drugs where accuracy is not a big issue
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what is intrathecal drug administration?
when drug is injected direclty into spinal subarachnoid space in order to bypass the blood-brain barrier
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2 ways to get to CSF for intrathecal drug admin?
- 1. end of spine - less likely to harm spinal cord
- 2. during surgery for pts with brain tumor
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4 factors that help predict the movement of a drug + its availability at sites of action?
- 1. molecular size + shape
- 2. degree of ionization
- 3. relative lipid solubility
- 4. binding to serum & tissue proteins
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why is the intestine the main location of drug absorption?
because its surface area is so big
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what kind of molcules cannot get past lipid membrane?
charged or hyperphilic molecules
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if drug's lipid solubility is high, _____?
partition coefficient is high > creates strong conc. gradient across the membrane > acceleratess drug transfer
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passive transport of drugs is directly proportional with what 3 things?
- 1. the magnitude of the concentration gradient across membrane
- 2. lipid-water partition coefficient
- 3. membrane surface area exposed to the drug
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facilitated transporters are passive BUT also?
selective and competitive
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carrier-mediated membrane transport
- facilitated transport
- uses transporters that dont use energy
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what happens when you increase drug concentration in faciliated transporters?
- at some point, transporter will get saturated
- increasing drug concentration will not increase transport rate
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how does ATP allow for active transport to occur?
ATP forces confirm. change of transporter > kicks out substrate to the other side
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secondary active transport
- indirect investment of energy
- uses electrochemical gradient to move a diff molcules against its concentration gradient
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how does Glutamate use secondary active transport to get into the cell?
- Na/K pump pushes Na+ outside the cell
- this creates waterfall effect of Na+ rushing back into cell
- Glutamate hitches a ride with Na+ (no direct energy used)
- once Na+ gets in > changes confirm. of transporter and falls off bc very little Na+ in cell
- transporter doesnt want Glu anymore and spits it out into the cell
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pinocytosis
when cell engulfs molecules into vesicles + releases contents inside of cell
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symporter vs antiporter
- symporter - transports molecules in same direction
- antiporter - transports molecules in diff directions
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bioavailability
how much of the ingested drug reaches intended area/blood circulation
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bioavailability depends on
- 1. absorption
- 2. first-pass metabolism
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drug given orally has to go through what?
- first must be absorbed in stomach and intestine
- then passes through liver (first-pass elimination)
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way to measure bioavailability (what fraction)
fraction of AUCpo / AUCiv
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4 ways drug is distributed to different compartments?
- 1. intravascular - drug stays in blood vessels, highest concentration
- 2. intravasc + interstitial - drug spreads out in both blood vessels & interstitial space, lower conc.
- 3. extra+intracellular - drug spreads out b/w blood vessels + interstitial space + into cell too
- 4. tissue binding - leaves vasc. completely, all in cells, no conc in blood vessels
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we can only measure concentration of drug in?
- in vasculature/blood stream
- not measurable in the cell
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why does drug conc. decrease over time
because it is being filtered out
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why is there an immediate drop in concentration when drug is injected through IV?
b/c its being distributed to other tissues
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order of tissues that drug is distributed to?
- 1. vasculature - falls rapidly with distribution
- 2. vessel-rich group (VRG) tissues - brain, heart, kidney, liver
- 3. muscle mass - larger but slower uptake capacity
- 4. adipose-rich group - most poorly perfused, can act as reservoir for some drugs
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body fluids can be divided into 3 compartments:
- plasma (3L)
- interstitial fluid (16L)
- intracellular fluid (38L)
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distribution of drug to diff tisues in body depends on what 3 things?
- 1. distribution of body fluids to diff organs - faster in organs that receive a lot of blood supply (liver, kidney, brain) vs oragans that receieve little supply (fat, bones)
- 2. prevention of entry into the brain - protected by blood-brain barrier
- 3. solubility of drug - determines its partition into fat vs. water/salt based tissues
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what prevents drugs from entering blood-brain barrier?
- tight junctions
- glial wrapping
- special transporters
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how is volume of distribution measured?
ratio b/w tota amount of drug in body (dose given) / the concentration of the drug measured in blood/plasma
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if the concentration of the drug in plasma = the concentration in rest of body, then vol of distribution will be
- the same as the volume of the body
- volume of dis = volume of body
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if drug doesnt like to leave serum, its concentration in the plasma is _________ and the calculated Vd is _________
- - disproportionally high
- - SMALL
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if drug gets concentrated in tissues, its concentration in the plasma ________ and the calculated Vd becomes _________
- - disproportionally drops
- - BIG
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what does Vd tell us?
the tendency of the drug to stay evenly distributed or accumulate inside/outside the serum
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if Vd is small, this means drug accumulates in?
the serum
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if Vd is big, this means drug accumulates in?
the tissues
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if a drug preferentially goes into or stays away from fat, then Vd might be unusal in what people?
obese patients
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function of blood proteins?
- serve as storage and buffering factor
- reduce free drug concentration
- prolong disappearance of drug
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major binding protein in the serum
Albumin
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how does binding to proteins affect drug concentration?
helps drug avoid high peaks and rapid decline --> longer effect but less of it
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how can pH affect drug concentration?
change in pH can change ionization state of drug > changes its permeability = ability of drug to cross membrane
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what happens when weak acid is placed in stomach?
acidic environment = lots of protons present > wont release proton > stays un-ionized > can penetrate membrane
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what happens when weak base is placed in intestine?
basic environment = less protons > less likely to pick up a proton > stays un-ionized > can permeate membrane
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definition of pKa
- the pH that gives 50% ionization
- aka the pH at which 50% of molecules are bound to the proton
- when pH=pKa, then proton donor conc. = proton acceptor conc.
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weak acid is unionized in
low pH
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weak base is unionized in
high pH
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how does an infection affect efficacy of local anesthetic?
- infection can resut in local acidification > if the env. beomes too acidic and anesthetic stays un-ionized in basic environments, it mght ionize and not be able to cross the cell membrane
- need to choose local anesthetic that will be able to stay un-ioinized and pass through membrane
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how can we estimate distribution of drug if we know pKa and pH?
can calculate how much of the drug is ionized vs. how much is unionized
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why are weak bases not as good at penetrating membrane as weak acids are?
- bc the intesine is slightly basic, but stomach is extremely acidic so its easier for weak acids to permeate
- BUT the surface of intestine is very large which helps w/absorption
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how does food intake affect absorption rate?
presence of food in stomach delays the emptying of the stomach to the intestine, which enhances or delays absorption depending on if drug is weak acid or base
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what happens when drug is taken PO with food?
- spends longer time in stomach
- good for absorption of weak acids
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what happens when drug is taken PO on empty stomach?
- quicker transfer to intestine
- good for absorption of base
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what is a good way to clear toxin from kidneys?
- make urine more acidic than blood using ammonium chloride > toxin moves to urine
- use bicarbonate to alkalize urine > promotes acid excretion
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