Pharmacokinetics (Ch 3) Flashcards
ADME
absorption
permeation
distribution
metabolism
excretion
describe the 4 ways a drug gets across barriers
- aqueous diffusion
- lipid diffusion
- special carriers
- endo/exo-cytosis
Volume of Distribution (Vd)
space available in body to contain drug
how much of the drug gets distributed to other areas in addition to just the bloodstream
Clearance (CL)
ability of body to eliminate the drug
this predicts the rate of elimination
CL = ROE/concentration
CL systemic is calculated by totaling the clearance of other organs (i.e. renal, liver, etc.)
Concentration (C)
the total amount of drug in the bloodstream
Rate of elimination (ROE)
ROE = CL x C
ex) drug = 75mg/L
clearance = 349 ml/min
ROE = CL x C
= 75 mg/L x 349 ml/min
= 75 mg/1000 ml x (349 ml/min)
= 26 mg/min
changes over time
Target Concentration (TC)
the steady state concentration associated with the target drug effect
aqueous diffusion
larger aqueous compartments (ECF – cytosol, interstitium)
aquaporins (water channels)
water soluble drugs cross by diffusion by [ ] gradient
molecules can be large (20,000 - 30,000 MW)
lipid diffusion
limiting factor for drug permeation bc there are many lipid barriers to cross
ability to move between lipid and aqueous phases is important for good drugs
sometimes weak acids/bases can become uncharged while passing the membranes and then become charged again, depending on the areas
ex) cholesterol can cross via lipid diffusion
special carriers
can keep exogenous things out of the blood stream (i.e. BBB) unless it’s the liver (the liver takes everything in)
molecules bind to drug and move across barriers
active transport and facilitated diffusion
ex) NET (norepi transporter)
ex) SERT
serotonin reuptake from synapse is normal, but SSRIs can inhibit reuptake of serotonin from synapse, which would keep serotonin in the synapse longer and would help with sx of depression
differentiate endocytosis and exocytosis
endocytosis - membrane engulfs drugs (i.e. clatherin coated pits)
exocytosis - merging of vesicle with membrane
Vd calculation
= dose/initial drug concentration in liters
what is meant by a “high Vd”
a high Vd means that more of that drug is leaving the blood (to other areas of distribution)
what is first order elimination?
CL is constant
ROE decreases over time (because the drug concentration decreases)
ex) 1000 mg of drug A bolused. after 1 hour, your body has removed 120 mg/60 min in the first hour, and your CL is 12%. you are left with 880 mg in your body.
in the second hour, your body removes 106 mg, leaving 774 mg left in your body, but your CL is STILL 12%.
standard whole blood volume in liters for a 70kg person?
5.6 L
standard plasma volume for a 70 kg person?
2.8 L
what is zero order elimination?
ROE is constant
CL increases over time
ex) you ingested 1000 mg of a drug at 0 hours. after 1 hour, your body has eliminated 150 mg, leaving 850 mg left in the body, and your clearance is 15%.
in the second hour, you eliminated only 150 mg of that drug again, leaving 700 mg left and your CL is 18%.
ROE is constant bc the body’s ability to eliminate the drug has reached its maximum capacity – it cannot eliminate the drug any faster.
what are 3 drugs that can reach zero order elimination?
APE:
ASA
Phenytoin
Ethanol
calculate tylenol’s dose
Vd = 67L/70kg
TC = 15mg/L
dose = (Vd)(TC)
dose = (67L/70kg)(15mg/L)
dose = 14.35mg/kg OR 1005 mg/70kg
in a 70kg patient, if aspirin has a Vd of 11 and carbamazepine has a Vd of 98, which drug stays in the blood more?
aspirin.
98 > 11, therefore, carbamazepine has a greater amount of drug that LEAVES the blood
calculate a lasix dose
Vd = 7.7L/70kg
TC = 5mg/L
dose = (Vd)(TC)
= 7.7L/70kg x 5mg/L
= 0.55mg/kg OR 38.5mg/70kg
half-life (T 1/2)
the time it takes the body to get rid of HALF the drug [ ]
T 1/2 = (0.7 x Vd)/CL
ex) 10 mg bolus given; T 1/2 = 4 hours. After 4 hours, there would be 5mg in the body. After another 4 hours, there would be 2.5 mg, etc.
steady state dosing
the amount in blood during constant rate admin after X amt half-lives; and the amount left in blood after stopping admin after X amt of half-lives
you’re giving JUST ENOUGH drug to balance what the body is eliminating; usually bolus is given FIRST and then steady state dosing
assumed to require 4x half-lives to achieve FULL effects of drug (or to see drug eliminated after stopping)
ex) if your T1/2 is 4 hours, it will take **16 hours **to get to TC (4hrs x 4 half lives, if NO bolus was given)
accumulation
very important for PO drugs
drug accumulates until dosing stops; you can reach toxicity very quickly! take as directed!
ex) if T 1/2 is 2 hours; you wait 8 hours (4 full half-lives) until the NEXT dose; we want to make sure the body is able to effectively eliminate the drug before next drug to prevent accumulation and toxicity
bioavailability (F)
Fraction of unchanged drug reaching systemic circ
7 routes of drug admin
- IV
- IM
- SQ
- PO
- PR
- inhalation
- transdermal
what factors affect bioavailability
physical properties of drug (hydrophylicity, pKa, solubility, etc)
forumulation/route
GI - diet, gastric emptying, transporters
polypharmacy
overall health/disease state (liver disease)
circadian
first-pass elimination
the liver will biotransform some drugs prior to reaching the systemic circulation (if given PO)
routes bypassing first pass-effect
IV
IM
SQ
Inhalation: has its own metablism (lungs have same enzymes as liver); has SOME first-pass effect
SL (blood vessels under the tongue)
transdermal (lipid soluble)
PR (some suppositories migrate upward, and therefore only 50% bypass hepatic circ)
target concentration
the [ ] that will produce the desired effect
factors are individualized to determine dose – what is the GOAL for the patient?
ex) digoxin
+2 ng/ml - controls afib
+1 ng/ml - manages HF
maintenance dosing: steady state dosing
dosing ratess = ROEss
OR
dosing rate: CL (l/h) x TC
dosing rate is usually mg/hr
maintenance dosing: bioavailability <100%
dosing rateoral = CL x TC/Foral
dosing rateoral = CL x TC/BIOAVAILABILITYoral
F = 0.X (usually a percent; 0.2 = 20%)
maintenance dosing: intermittent doses
maintenance dose = dosing rate x dosing interval
maintenance dose = CL x TC x (time interval in hours)
you have to give more if the bioavailability is less!
loading dose
LD = Vd x TC
slow admin is key – fast enough to reach steady state quickly, but not so fast that it doesn’t have time to distribute
assumed if given over 5 mins
peak and trough
3 draw types:
1. peak (5-10 min after IV drug admin)
2. trough (30 mins PRIOR to next dose of drug)
3. random (any time)
pts own enzymes can transform drugs, so individual response should be monitored
ideal body weight
Vd calculated using body weight
drugs that do not penetrate fat
“preferentially in serum”
IBW
men = 52 + 1.9kg x inches over 5 ft
women: 49 + 1.7kg x inches over 5 ft
ex) 5 ft 5 male pt weighing 120 kg would have an IBW of 62 kg (52 + (1.9 kg x 5))
creatinine clearance
muscles produce a steady amount of creatinine – a breakdown product of creatine in the muscles
everybody produces around the same amount at the same time (except for body builders/crush injury patients, etc)
the creatinine clearance gives us a picture of the overall health of the kidneys
