Principles Of Drug Therapy 3 Flashcards
What drugs won’t be filtered?
Those bound to albumin
>50K mw
The amount of a drug filtered depends on?
- Filt fraction (20%): can vary w/age and disease
- % bound to albumin or other proteins: since water is filtered, the conc of free drugs in unfiltered plasma doesn’t change so no dissc from albumin
What is active tubular secretion?
Needed for albumin bound drugs
PCT: charged drugs actively transported into lumen
Free conc of drug in peri tubular cap decreases bc PT reab 2/3 of filt water
Drugs with like charges compete bc on interactions
What is reab, how+where?
Salt and water actively reab
- drugs conc in urine
- drugs in plasma diluted
- reab gradient
Reab if good PC (so, non ionic diff), 3 Ps
-if drug has low water solubility, may precip leading to tub obstruction
Handling rules?
Charged: secreted
PC: reab
Size and extent of protein binding: filtered
How is inulin handled?
It’s a fructose polymer
Small, filtered, doesn’t bind (fraction filtered = filtration fraction)
No charge
0 PC
Amount in urine reflects that filtered
GFR x [inulin]plasma = UFR x [inulin]urine
or
GFR = UFR x [inulin]urine/[inulin]plasma
Renal handling of penicillin?
It’s a weak acid
354 mw, small
40% free, frac filt = filtration fraction x 0.4
Actively secreted
0 PC, no reab, excretion not pH dependent
30 min half life
Why is probenecid used? Properties?
To prolong penicillin half life, uric acid excretion in gout
Secreted, good PC, 90% bound
- 285 mw, 10% free frac filt = filt frac x 0.1
- anion actively secreted in PT, competes
- good PC, reab in DT
- long half life 5-8hr
- blocks pen secretion
Summary of drug renal handling?
Drugs w/ 50mw+ filt unless bound
Charged can be substrates for A+ trans in PT
Weak A and B will be reab in DT in pH dependent manner
Neutral w/ good PC will be reab
GFR and tub secretion is low in babies, old, disease ppl leading to lower drug elim
How to elim drugs w/:
Poor water solubility?
Bound?
Reabsorbed?
Poor substrates for anion/cat pumps?
Biotransformation and conjugation
What is biotransformation?
Modify drug to make it more water soluble and less lipid soluble so it will eliminated
What are the phases of biotransformation?
Phase I: Chem modification
Ox or hydrolysis
Inactivation, some A+
**CYP450 (lipophilic stuff oxidized)
Phase 2: Conjugation
Adding hydrophilic substance
Gives low PC
Inactivates, makes less toxic
P450 features?
57 functional, into families and sub fam
-Each w/ diff selectivity, needs lipid soluble substrates but otherwise low selectivity
-slow rxn/turnover rates
OFTEN RATE LIMITING STEP!!
Most A+ and important CYPs?
CYP 3A, 2D, 2C
Most important in liver: 3A4 (>50%), 2D6 (20%)
How do some drugs stimulate or block metabolism of other drugs via CYP enz?
By inducing or I- certain CYPs
Barbiturates: 3A4, 2C9
Inducing: Can lead to tolerance
Cimitidine I- metabolism of many drugs, 3A4 is I- by ketoconazole, erythromycin, ritonavir, grapefruit juice
2D6 is I- by SSRIs (fluoxetine, paroxetine)
2D6 polymorphisms?
Poor/ultra rapid met
Tricyclic antidepressants
Dextromethorphan
What is conjugation?
Adds a group to drug
-glucuronate, sulfate, glutathione
Inactivates drug (except morphine and minoxidil)
⬆️rate than phase 1, ⬇️PC
*65% of acetaminophen inactivated by glucuronidation in adults
Effects of glucuronidation?
Adds - charge
Makes more water sol
Less binding to albumin, more filtration
Prod is substrate for active anion trans (secretion) in kidney and liver
Poor PC, so no non ionic reab
Why is conj important?
Most drugs inactivated, elim happens, some A+ (morphine)
Diff in conj is source of drug response variability and cause of diseases
Liver blood flow? What happens to drug in the liver?
HPV to HA to central vein
Cells near sinusoids extract drug
Parent or metabolized drugs may pass back to blood or bile (biliary excretion)
Pass diff and A+ trans
What happens to the drug after biliary excretion?
If poor PC: stay in GI, then into feces
If good PC: reab, back to liver
What happens to drugs conj w/ glucuronic acid?
Have bad PCs
Colon bacteria can remove glucuronic acid
If good PC: reab to liver, reconj, back to bile **ENTEROHEPATIC CYCLING!!
What are the consequences of ENTEROHEPATIC cycling?
Half life ⬆️, good for active drug
Kidney might elim
Agents that block cycling by preventing reab can ⬇️ 1/2 life of cycling drug **interaction
(antibiotics that kill bac, charcoal, non abs polymers)
Does dose relate to protein binding?
No change in dose
What happens when 2nd drug i- elim of 1st?
⬆️ plasma conc of 1st, so may need to ⬇️ dose
Kid or liv disease may⬆️ conc of elim drug require⬇️ dose
What happens when 2nd drug stim elim of 1st?
⬇️ plasma conc, will need to ⬆️ dose
