what are the fundamental questions regarding medication? 3
how to deliver, what concentration, how long should the medication be taken for
what are the benefits (2) and drawbacks (1) of topical medication admin
Topical: + immediately effective, long lasting, - most most drug action sites are internal
what the body does to the drug
what are the four factors affecitng pharmacokinetics
ADME. Absorption, Distribution, Metabolism, excretion
what are seven common routes of drug admin?
1. oral 2. IV 3. Topical 4. rectal 5. injection 6. inhaled 7. sublingual
what is the first-pass effect
drugs that are absorbed through the GI tract must first pass through liver before going to systemic circulation. the liver detoxifies some of the drug and concentration decreases
what are four ways in which oral drugs are lost?
1. stool 2. detoxed by liver 3. binds plasma proteins/ends up in adipose (free drug=active drug) 4. excreted
what does MEC stand for? what are the two types associated with drugs?
minimum effective concentration. MEC for desired response. MEC for adverse response.
what is the therapeutic window of a drug?
between MEC for desired response and MEC for adverse response
most drugs are absorbed actively/passively due to their _____/____ nature. this type of absorption is/ is not saturable and therefore displays ___ order kinetics
passively hydrophobic/uncharged (easily pass through membrane) not saturable first order kinetics
the pKa for a weak acid is...
the pKa for a weak base is
most drugs are what type of acid or base?
weak acid or base
what form of WA/WB are readily absorbed
when decreasing pH what form does WA/WB take
WA: HA (uncharged) WB: HB+ (charged)
when increasing pH what form does WA/WB take
WA: A- (charged) WB: B (uncharged)
Aspirin is a weak acid drug, will increasing intestine pH increase aspirin absorption?
decrease absorption HA+H20==>A- + H3O+ (more of the deportonated charged form)
what is bioavailability?
the amount of an oral drug that actually reaches systemic circulation and can be used by the body
if given a graph of [plasma drug] vs time of an injected drug and orall drug, how can you calculate the bioavailability
BA: Area under curve oral/AUC injected X100
what factors limit the bioavailability of a drug? 5
some drugs are degraded in acid of stomach, some drugs are not efficiently absorbed in GI tract, micororganisms in GIT metabolize drugs, first pass effect
what factors impact the distribution of drugs in the body? 4
blood flow, capillary permabeability, binding of drugs to plasma proteins/tissues, hyrdrophobic/hydrophilic drugs
how does blood flow impact drug distribution?
some organs receive more blood flow (brain, liver, kidney>muscle, skin, fat) and therefore more exposure to drugs in circulation
how does capillary permeability impact drug distribution?
some capillaries are less permeable. brain capilllaries less permeable than liver capillaries
what is a drug resevoir?
drugs bind plasma proteins and in tissues, these drugs are not active. when the free drug concentration decreases, these drugs will be released.
what are the two "compartments" of the body/
central compartment (circulation), peripheral compartment (body tissues)
what is the alpha phase?
an initial rapid decline in [plasma drug] that is a result of body tissues binding/sequestering drug. eventually an equilibrium is obtained
what is the beta phase?
decrease in drug concentration due to removal from the body (metabolism/excretion)
what is the volume of distribution?
how much drug needs to be put in the body to get a certain [plasma drug].
what is the eqn for Vd
Vd=amount of drug in the body (amount given, mg)/drug concentration in plasma (mg/L)
a 70 kg man has how many liters of plasma? liters of blood?
3 L of plasma, 5.5 L of blood
drug metabolism GENERALLY activates/inactivates a drug
the enzymatic modifications of drugs typically make the drug more...
hydrophilic/polar so they can be excreted
what is a prodrug?
a drug that is inactive but activated by metabolism
where does drug metabolism mainly occur?
what are the two phases associated with drug metabolism?
Phase I, phase II
what is a phase I reaction? main enzyme?
oxidation, hydrolysis, hydroxylation, dealklylation, deamination. CYTOCHROME P450s (odxidation, reduction, hydrolysis)
what is a phase II reaction?
addition of a large substituent group (glucuronyl, sulfate, acetyl) that makes the compound more POLAR
Cytochrome P450s: location, role, typical structural feature of substrates
most important enzyme for drug metabolism, over 57 P450s in human genome. located in membrane of ER (mainly in liver), high lipid solubility is a common structural feature
general rxn that CYP (cyt P450 catalyze)
NADPH+ H+ +R +O2==>NADP+ + H2O + RO
microsomal (ER) enzymes can be activated by... (3 examples)
repeated exposure to some drugs: ethanol, phenobarbital, carcinogenic cmpds
microsomal enzymes can be inhibited by....(3)
decrease activity of CYP. Imdazole containing drugs, some antibiotics, grape fruit juice
how many Cytochrome P450s account for 95% of drug metabolism? which is the biggest contributor
6 Cyt P450 enzymes. CYP3A4
what is the M-M eqn?
v=(Vmax[C])/(Km+[C]), [C] is drug concentration
when [C]>>>>Km, what does the M-M eqn look like? what order kinetics?
v=(Vmax[C]^0); zero order reaction. V is independent of [drug]; saturated (drugs that need a transport protein)
v=(Vmax[C])/(Km); first order reaction. V is dependent on drug concentration; non-saturated (passive diffusion of drugs)
most drug elimination resembles which order kinetics?
first order, the rate (-dC/dt) of disappearance is dependent on the concentration of the drug
what is the integrated rate law for 0 order reactions?
what is the integrated rate law for a 1 order reaction?
the rate of disappearance for a drug having zero order kinetics is...
-dC/dt=k; elimination has become saturated
the rate of disappearance for a drug having first order kinetics is....
-dC/dt=K[C]; elimination is not saturated
what is half-life of eliminaiton?
the amount of time required for the concentration of drug in the blood to decrease by 1/2
what is t(1/2) for a first order reaction
what is t(1/2) for a zero order reaction?
what is clearance?
CL; the volume of plasma cleared of the drug per unit time (L/hr)
does clearance for most drugs depend on concentration of the drug?
YES! most drugs depict a first order elimination. -dC/dt=kC
what equation related CL and Vd?
what equation relates half life (first order), Vd, and CL?
a pt took 10 mg IV injection of a drug and the plasma drug concentration was 1 mg/mL. 10 hrs later the drug concentration was .25 mg/L. what is CL
what is the (Css) steady state concentration of a drug?
seen during drug accumulation (repeated dose of a drug, contstant rate IV), this is when the rate of infusion=rate of elimination (first order reaction, the concentration of the drug gets high enough where its eliminanation matches its accumulation)
If rate of infusion (IV infusion) increases then what happens to Css
Css increases (directly proportional, double rate=double Css)
if the clearance of a drug increases (is doubled) what happens to Css?
Css halves (inversely proportional)
when do we see CL decrease?
liver or kidney disease
what is clearance?
how fast the drug is eliminated from the body
what determines the time to reach the steady state? exception?
changed only by factors that change t(1/2). only factors that alter elimination (increase metabolism of a drug or increase clearance will both decrease the amount of time to reach Css). Exception is a loading does that will attain Css faster due to a higher initial dose
a pt takes a drug with regular repeated oral doses. which may result in shorterr time required to reach Css? 1. shorten the dose interval by 50% 2. increase drug dose by 2x 3. take a drug that induces the P450 enzyme 4.take a drug that inhibits P450
3. inducing P450 will increase the CL and the Css will be reached faster
changing the rate of infusion of a drug changes the final Css/time to Css, but does not alter the final Css/ time to Css
changes the final Css does not change time to Css
relate Css value and frequency of dose (oral) and interval of dose
Css=frequency/interval of dose as frequency increases, Css increases as interval increases, Css decreases
relate Css value and dose of a drug
Css is directly proportional to dose. increase dose, increase Css (the time to Css does not change!!)
if a drug is not metbaolized by the liver very well, what is a possible side effect?
the drug accumulates in the body
rate of elimination=
CL x [C]
onset of effect, topical admin, oral admin, duration of action, peak effect, intensity, MEC for advers, MEC for desired, therapeutic window