Drug Excretion Flashcards
Kidney glomerular filtration
- about 10% of renal arterial blood supply gets filtered
- normal GFR 120-130 mL/min
- no cells or proteins larger than 60-70 kD
- unbound drugs are freely filtered at glomerulus
- amount of drug entering tubule lumen depends on GFR and extent of binding to large proteins
tubular transport
- modification of glomerular filtrate to form urine
- active transport from urine is important for Na, Cl, HCO3, glucose, and AAs, but not xenobiotics
- endocytosis is important for proteins and polypeptides that are filtered, get reabsorbed by cells in proximal tubule (if drugs attached they go with)
Passive reabsorption
- passive movement of substances from tubular fluid to blood
- 99% of H2O reabsorbed; follows salt passively
- lipophilic substances will diffuse back into blood as their tubule [ ] increases
- hydrophilic substances remain in tubule and become more concentrated as H2O reabsorbed
- weak acids and bases will leave if not charged (depends on acidity/basicity of urine) (eg methamphetamine=weak base-acidify urine to excrete)
Active secretion
- active transport from plasma to urine
- ATP-binding cassette transporters
- organic anion (acid) and cation (base) secretion (ionized at physiological pH)
- these transport systems can “strip” drugs from the proteins they are bound to: as drug is secreted into tubule, more dissociates from the protein to maintain equilibrium
Bile
- contains H2O, electrolytes, and organic molecules including bile acids, cholesterol, phopholipids, and bilirubin
- adults produce 400-800 ml daily
- active transport from plasma to bile-transport systems in cancalicular membranes of hepatocytes
- ABC transporters, organic acid and base transport systems, neutral compounds (ouabain)
- min molecular weight for active transport 275-375 (conjugation may help)
- metals: Mn, Hg, Cu, Zn, Cd
dose
= amount at absorption site + amount in body + amount excreted + amount metabolized
Zero order
- rate of change is independent of amount of drug present (eg when enzyme is saturated)
- few drugs exhibit 0 order kinetics under normal conditions; alcohol, phenytoin exceptions
First Order
- rate of change is directly proportional to amount of drug present
- most drugs
volume of distribution
-apparent volume of distribution determined at time 0
=A/C
-small Vd-> (larger C) drug highly bound to plasma proteins (can’t have smaller Vd than plasma volume)
-large Vd-> (smaller C) drug distributed into tissues
-plasma may contain only a small fraction of total body load
States that may alter Vd
- Uremia (excessive uric acid in blood), burn pts -> decreased albumin binding -> higher Vd
- Pregnancy, ascites, edema -> decreased plasma [ ] -> higher Vd
- dehydration -> increased plasma [ ] -> decreased Vd
- CHF, end stage renal disease -> decreased clearance of drugs excreted by kidneys -> may increase or decrease Vd
Elimination half life
-time taken for plasma [ ] (not amount or therapeutic effect) to fall by 1/2
-after 5 half lives, virtually all the drug is eliminated
t1/2=.7/Ke (elimination rate constant)
Factors affecting drug half life-Vd
- decreased total body H2O (aging, dehydration) and muscle mass (aging)->decrease Vd->decrease t1/2
- obesity->increase tissue binding->increase Vd and t1/2
- increased nonvascular fluid (pregnancy, ascites, edema) -> increase Vd and t1/2
- decreased albumin (hepatic disease, uremia, burns) -> decrease protein binding-> increase Vd and t1/2
Factors affecting drug half life-Clearance
- CYP induction-> increase metabolism -> increase CL-> decrease t1/2
- CYP inhibition->decrease metabolism and CL->increase t1/2
- Cardiac, hepatic, or renal failure-> decrease CL->increase t1/2
Factors affecting drug half life
- Vd
- Clearance
- multiple equilibria-amount albumin bound, stored, and eliminated
Constant rate infusion
-Goal is to maintain a stable plasma [ ]
-want rate of infusion (steady state) = rate of elimination (steady state)
=> rate of infusion = CLsteady state [ ] C
=> amount in body = Vdsteady state [ ] C
