Elimination Flashcards
(29 cards)
T or F: most drugs are too lipophilic to be excreted unchanged
true - must be metabolized first
Mechanisms of elimination
Metabolism: liver and gut
Excretion: included elimination of unchanged drugs (generally done by kidney, can also be done by bile)
What do you have to take into account when calculating Cl
Elimination done by all organs
- renal and non-renal , need to add them together
- renal: can measure excretion via drug in urine
non-renal: no way to measure directly, generally assume is hepatic Cl
What is the primary determinant of maintenance dose?
Cl
What type of process is elimination normally
first order
- rate controlled by conc
- metabolism: done via enzymes (MM kinetics) where velocity of reaction increases with conc until reach Vmax (enzymes at max capacity)
What is the MM equation
Rate = Vmax * Css/ Km + Css
- Vmax: max Rate of metabolism
-km: conc of drug at which rate is 50 % of V max (inversely related to ka/affinity)
** non linear relation bw Css and R
generally km» Css so R= (Vmax/Km) * Css
What is hepatic BF
1.5L/min
- max value for hepatic Cl
- blood enters via portal vein (75%) and hepatic artery, empties into sinusoids , hepatocytes metabolize shit and leaves via vein and IVC
Drug Metabolizing Enzymes : main
CYP 3A4/5 and UGT - 75% of metabolism
Main enzyme involved in Phase 1 rxns
sometimes need P1 rxn to get pharm activity
normally CYP P450
- polymorphism present in their ability to metabolize
- 3A4: main boi, can take place in enterocytes and liver
P II reactions
synthetic rxns that add subgroups to drug to increase polarity
-glucuronidation
Biliary Excretion
excreted in bile and the via GI
- more commonly used for drugs that are more hydrophilic and larger MW (> 300)
- normally things that are glucornidated
- flow rate is super slow (1mL/min) — low Cl rate unless conc in bile»_space; plasma or if actively secreted into bile
—- increase conc in bile and Cl
** conc determines Cl via liver
Elimination via kidney processes
1) filtration in glomerulus
2) active secretion in PCT
3) reabsorption in DCT
T or F: BF to kidney is faster than to liver
F - renal Q is 1.2L/min
hepatic 1.5L/min
What is renal plasma flow
Renal * (1-HCT)
What is average GFR
125mL/min
What influences glomerulus filtration
passive movement from blood to tubule/urine
-influenced by GFR and PPB , MW
What influences secretion
active movement from blood to PCT
influenced by WA, WB, competitive inhibitors of transporters (OAT, OCT)
What influences reabsorption
can be active or passive in DCT
influenced by lipophilicity, degree of ionization (pH) and urine flow rate
Urine Formation/Filtering
normally : vitamins, electrolytes, and glucose are reabsorbed
MW cutoff for filtering: only MW < 20,000 passes through filter
- anything protein bound : doesn’t go into urine
most of the filtered plasma is reabsorbed so urine flow rate is slow —- 1-2mL/min
How to get Clrenal
Cl renal = Fu* GFR
- equal if no secretion or reabsorption occurring ( increase in PPB—- decrease renal Cl)
How to tell if secretion is happening
Cl renal > fu * GFR
—- more drug being moved out than based on the amount unbound and the filtering rate
Reabsorption
Cl renal < fu * GFR
- less being moved out then we thought
- passive process driven by conc gradients, lipophilicity (more lipophilic - more likely to be reabsorbed), using flow rate (move faster, less reabsorption) , degree of ionization (not ionized - more likely to be reabsorbed)
T or F: if a WB is more ionized in acidic pH — it is more likely excreted
T - if ionized; less likely to be reabsorbed
urine pH generally more acidic than plasma
Can we calculate Clrenal
Yes - if get plasma data and urine concentration data
- collect over t1/2 5X , collect urine at set intervals
- ln (Excertion) vs t = slope = -k
log (excretion) vs t = slope = -k/2.3
semi log : plot conc vs time; slope = -k/2.3
