Pharm 4. Flashcards
What is the most important route of elimination of drug or metabolites?
renal excretion
Amount drug excreted = ?
(amount entering tubule) - (amount reabsorbed) OR (glomerular filtration + active tubular secretion) - (passive reabsorption + active reabsorption)
How do drugs enter the nephron?
glomerular filtration (only free drug molecules filtered), and active tubular secretion
When does saturation for active tubular secretion happen?
at therapeutic doses or with over doses
How doe saturation change the process?
from a 1st order to a zero order process
What is the equation for a first order secretion?
V = Vmax [D] / Km + [D]
What is the equation for a zero order secretion?
V = Vmax
How are drugs reabsorbed?
passive reabsorption (esp lipid soluble) and active reabsorption
What type of drug is most easily eliminated?
water soluble drugs
What do lipid soluble drugs need to be excreted?
phase I and sometimes phase II transformations
How can renal excretion be enhanced?
forced diuresis or manipulate the pH of the ruin to trap ionized drug in urine (higher pH will trap ionize a lipid soluble drug)
What is commonly used to alkalinize the urine?
sodium bicarbonate
What are other routes of drug elimination?
bile, lung, sweat, saliva, tears, breast milk
What are the methods of elimination of drugs from site of action?
redistribution, biotransformation, excretion
Total clearance = ?
clearance metabolic + clearance renal
How is total clearance affected in hepatic disease?
reduced, esp metabolic (reduced in renal as well)
What determines the elimination rate constant (ke) for a drug?
rate limiting step
What are 6 factors influencing clearance?
- body surface area 2. protein binding 3. cardiac output 4. renal function 5. hepatic function 6. blood flow to systemic organs
inulin
used to estimate glomerular filtration rate (all is filtered, none reabsorbed or excreted)
glucose
all should be reabsorbed - effectiveness of reabsorption
PAH
approximates renal blood flow - all is filtered and secreted
What can be determined using the volume of distribution and clearance?
how often to dose a drug, what size dose to give, how long to expect a dose to last, when to re-dose a drug to sustain effect
On the logCp/time graph, what is alpha and beta respectively?
alpha: distribution (leaving volume initial); beta: elimination (liver/kidney/both)
ka
absorption rate constant
ke
elimination rate constant
How is ke determined?
by the rate limiting step in clearance (either metabolic or renal)
What is happening at max intensity?
absorption and elimination of drug are equal
How are zero order drugs related to absorption rates?
carrier mediated with saturated carrier protein at Vmax - not sensitive to drug concentration
How are first order drugs related to absorption rates?
absorption is sensitive to drug concentration
What do absorption kinetics tell us?
how much dose to give
What equation describes zero order rate? What is the slope?
Ct = k’a t (an amount absorbed per unit time) slope = ka (straight line)
What equation describes first order rate? what is the slope?
Ct = M/Vd X (1 - e ^-Ka t) (a proportion of unit time) slope = log slope
zero order elimination
an amount per unit time - is saturated (at Vmax)
What is the danger with zero order elimination?
have to be careful with toxicity - small changes can make a drug toxic
What is an example of a drug with zero order elimination?
alcohol - .02 eliminated an hour
When Ct
first order rate
When Ct»_space; Km
zero order rate
Half life applies to……
first order elimination kinetics
T1/2 equation
t1/2 = 0.693 / ke —> A CONSTANT NUMBER THAT CAN BE LOOKED UP IN A BOOK!
If clearance of a drug is large then the half life is….
small
Steady state
drug enters a compartment at a constant rate and is eliminated in a manner proportional to the concentration in the Vd. when the elimination increases to equal the rate of entry = steady state
How many half lives does it normally take to reach steady state?
4
Single doses casues what?
no steady state - dose interval is much greater than t 1/2
Repeated administrations causes what?
steady state (plateau) level - dose interval is less than or equal to t 1/2
Does route of administration affect Css average?
NO - you still need 4 half lives to get to steady state
Does dose affect time to achieve steady state?
NO SHUT UP
Fast elimination rate = ?
fast to steady state (slow elimination rate = slow to steady state)
How does achievement of steady state compare to elimination?
mirror image (takes 4 half lives to eliminate from steady state
What is the loading dose?
rapid attainment of therapeutic plasma level (not steady state) - need maintenance doses to keep at steady state
Iatrogenic
predictable adverse drug reaction - may be dose dependent
Spontaneous
not predictable - not dose dependent. includes allergies (once they occur once though they become predictable) and idiosyncratic
tolerance
decreased response to continued administration due to receptors and/or metabolism
cumulation
drug administered faster than it can be eliminated
ED50
effective dose in 50% of the population
TD50
toxic dose in 50% of the population
LD50
lethal dose in 50% of the population
Margin of safety
TD50 - ED50
Therapeutic Index
TI = TD50 / ED50
What is the ideal clinical for therapeutic index?
TD 1 / ED 99
What is a good therapeutic index?
larger the number the better - more doses between therapeutic window and toxicity
What will changing the pH or other electrolytes do?
alter excretion or protein binding
How is excretion changed?
active transport inhibitors or simple competition for a transporter
How is metabolism changed?
induction or inhibition
What does protein binding and displacement have the potential of causing?
toxicity
How is absorption changed/
charcoal binds drug molecules - decreases absorption
What are examples of direct molecular drug interactions?
antibiotics and calcium
