Pharm 224 Midterm (theory)

What is pharmacokinetics?

body → drug

What is pharmacodynamics?

drug → body

What parameter determines dose?

clearance

_________ drugs are a type of drug that takes long to show effect

prophylactic

What makes dosing difficult?

patient variability/factors

What is the biggest issue with medication?

adherence

Briefly outline PK for drug development

Pre-clinical: in vivo (hepatocytes, absorption, animals for dose)

Phase I: health adults, determine DOSE

Phase II: avg PK values and variability

Phase III: population models, determine co-variants and standard dose

Where is [drug] commonly measured from?

plasma

can use serum (coagulated) or whole blood (temp not factor)

Sampling time interval depends on

drug half life

What is

onset:

duration:

intensity:

how quickly to MEC

how long >MEC

Cmax (peak)

On a conc vs time curve, what does AUC represent?

drug exposure

For sampling, you should always collect _______ half lives

4-5

What factors impact dissolution?

pKa, size, solubility

What is 1st pass effect and where does it occur?

loss of drug from liver

T/F distribution is irreversible

F

What does distribution depend on?

size, lipophilicity, plasma protein binding

Why do seizure drugs need high lipophilicity?

need to enter brain

Overall, what do phase I and II reactions do?

make drug more polar for easier excretion

What is responsible for most drug metabolism?

CYP3A4/5 and UGT

This organ is responsible for majority of excretion

kidneys

When does biliary excretion occur?

drugs MW >300 and phase 2 metabolites

What is enterohepatic recycling?

glucuronide conjugate, hydrolyzed back to parent drug and reabsorbed

T/F the concentration vs time graph for IV dose is linear and follows 0 order elimination

F, usually curve that follows 1st order

T/F the fraction eliminated is constant

T

T/F the rate of elimination is constant for IV

F

How do the graphs of 0 order and 1st order differ?

0 order has linear conc vs time

1st order has linear log conc vs time

What does k = 0.45 mean?

45% of the drug is eliminated per hour

T/F you should use ALL points when calculating k

T (unless two phase then exclude distribution phase)

For a ln [ ] vs time graph, what is k and C0?

k = -slope, C0 = ln (y int)

For a log [ ] vs time graph, what is k and C0?

k = -slope*2.303, C0 = log (y int)

From a graph on semi log paper, how do you calculate k?

find slope using (ln y2 - ln y1)/t2-t1 and k = -slope

T/F a one compartment model is linear and follows 1st order elim on log conc vs time graph

T

When is the highest [ ] for one compartment model?

at t = 0

T/F k can range from 0 - 10

F, 0-1

Half life gives us

dosing interval and time to steady state

T/F clearance is the volume of blood reversibly removed by kidneys

F, irreversible

Clearance relates to ______ and can be calculated using what method?

AUC, trapezoidal rule

Using the trapezoidal rule, how can you calculate AUC?

(C0+C1)/2*t1 + (C1+C2)/2*(t2-t1)…+(Clast/k)

T/F the extrapolated area (last portion calculated using Clast/k) should be <25% of the total AUC

F, <10%

T/F Vd and Cl can be infinitely large

F, only Vd has no limit

What is the limit on Cl value?

upper limit cant be > Q

What is the lower limit for Vd?

plasma volume

A patient has a condition that doubles Vd of drug X. How does this affect Cl and t1/2?

no impact on Vd (Cl and Vd are independent)

double t1/2

T/F Given Cl = k*Vd, the variables on the right hand side are independent

F, k = Cl/Vd separates k (dependent) and Cl/Vd (independent)

What is the AUMC?

area under moment curve (under conc*time vs time curve)

What is MRT?

mean residence time, time drug spends in body

T/F half life is longer than MRT

F, MRT > t1/2

What is MAT?

mean absorption time, how long to absorb drug after admin

MAT = MRT(oral) - MRT(IV)

T/F two compartment model follows biexponential pattern

T

What are the two phases of a 2 compartment model?

distribution (rapid)

elimination (slower)

Which phase should you use to calculate k?

elimination phase

What is a drug that follows two compartment model?

digoxin

T/F the max effect of the drug is not the same as max plasma [ ]

T, max effect when drug is at target tissue

In a 2 compartment model, describe what is represented by the variables

A term = dist phase

B term = elim phase

beta = elim rate

B and A are y int

How do you calculate C0 for two compartment model?

A + B

T/F “A” represents the value from the x-axis to A

F, only extrapolated from elimination line

Drug transport depends on what 3 factors?

drug permeability

membrane SA

conc difference

T/F transcellular transport usually occurs for large drugs

F, paracellular

Permeability is greatest for drugs that are

lipophilic (high O/W)

unionized

low MW

For drugs with great permeability, distribution is limited by

perfusion

Distribution is faster in _______ perfused tissue 

highly (ex: liver/kidney

T/F distribution is fast in fat since it is highly perfused

F, slower

T/F the brain is highly perfused but is permeability limited

T, BBB

What types of drugs can pass the BBB?

lipophilic

T/F the brain, placenta, liver and kidney have efflux transporters that limit distribution

T

Aminoglycosides have large Vd and half life in patients with increased ECF or renal failure. What do you need to do?

decrease initial conc

T/F lipophobic drugs have larger Vd in obese

F, lipophilic

Total body H2O =

60% IBW (40-45L)

Blood volume =

7-8% IBW (5-6L)

Would the following drug have a small or large Vd?

large MW, hydrophilic, highly protein bound

small

What are 2 major plasma binding proteins?

albumin and alpha 1 acid glycoprotein (AAG)

Describe albumin

bind acid + basic drugs, 70kDa, most abundant, hard to displace

What are some drugs that can displace albumin?

salicylates, valproic, heparin

Describe a1-acid glycoprotein (AAG)

bind basic drugs, 40kDa, acute phase (increase in itis)

T/F AAG does not often fully saturate binding sites

T, except disopyramide

Describe causes of low albumin

renal or liver disease, burns, malnutrition, post op

Describe causes of high AAG

MI, RA, trauma, burns

T/F excretion is the removal of unchanged drug

T

T/F clearance is a volume term

T

Clearance is the sum of

non renal + renal

How do you calculate renal and non renal Cl?

renal Cl can calculate directly, non renal cannot calc directly

What does clearance determine?

maintenance dose

What model does metabolism follow?

Michaelis Menten, 1st order, plateau = Vmax

Where does metabolism take place?

endoplasmic reticulum of hepatocytes

What are the 5 main P450 enzymes?

CYP1A2, 2C9, 2C19, 2D6, 3A4

Which P450 enzymes are pharmacogenetic?

2C9, 2C19, 2D6

T/F Irinotecan treats tumours and undergoes activation by P450 then metabolized by UGT (glucorindation)

F, undergoes activation by ESTERASE

What helps with biliary excretion?

P-glycoprotein (MDR)

What is the cutoff for molecule size in urine?

<20kDa (proteinuria is problem)

Filtration occurs in the _________ by _______ transport and is influenced by ______, _______ and _______

glomeruli, passive, GFR/protein/MW

Secretion occurs in the ________ by _______ transport and is influenced by ________, ______________

PCT, active, acid-base/inhibitors of OAT/OCT

Reabsorption occurs in the _______ by ____________ transport and is influenced by _________ and ___________

DCT, active or passive, lipophilicity/ionization

How to determine if secretion or reabsorption is occurring in kidneys?

Compare Clrenal to fu*GFR

Clrenal < fu*GFR means

reabsorption

Clrenal > fu*GFR means

secretion

For a WB, how does acidic urine impact its reabsorption/excretion?

WB more ionized in acid, less absorp, more excreted

How does probenecid treat OP?

block UA reabsorption (OAT) to increase UA excretion

What should you consider when using creatinine to measure Cl?

overestimate, slight lag, impacted by dehydration and non representative height

Cockgroft is a monogram which means what

the units dont match on left and right side

Clearance is a product of

E and Q