Pharmacokinetics-2 Flashcards
Urinary filtration: general
- both ionized and non-ionized forms of drugs filtered there
- drugs bound to large plasma proteins > 45000 are not
- levels of resorption is dependent on [gradient], and ionization state (only lipid sol. forms absorbed)
Glucuronidation
Hydrolyzing drug products in the liver to return to circulation after absorption in the gut via secretion int the bile.
- morphine
- digoxin
- rifampicin
- PCP
Filtration in the tubule by location
- capsule, passive re-absorption of lipid soluble and non-ionized drugs
- PCT: active secretion of organic acids and bases
- DCT: passive resorption of lipid soluble and non-ionized drugs
Organic acid active transport molecule
For ionized organic acid resorption in kidneys (uric acid and salycilate would compete for this transporter)
- relatively non selective
- probenecid inhibits this system
- bidirectional process but secretion predominates
- Only free drugs are filtered
Inulin and creatinine
Both good approximate of GFR
- not secreted (creatinine is 10-15%) or absorbed
Clearance based on inulin/clearance
UV/P
- (urine [compound])(urine excreted)/[compound at midpoint of collection interval]
- normal adult ~ 125ml/min
- most accurate/least practical
Drug Clearance time (125 mL/min men; 100 mL/min women)
- Any drug with a clearance greater than 125 mL/min is being actively excreted into renal tubule
- any drug with a clearance less than 125 mL/min is being reserved, being bound to plasma proteins or distributed to depots. (Glucose clearance is ~ 0 hence it’s all secreted back into blood)
CrCl (CG formula)
(140-age)(weight in kg)(.85 if female)/(72xplasma creatinine)
IBW
50kg + 2.3(inches over 5 feet)
Metabolite effect on secretion
Metabolites tend to be more polar, thus increasing excretion
Non-synthetic (Phase I rxns)
Oxidation
Reduction
Hydrolysis
- inactivates, alters or ignores some drugs
- increases hydrophilicity by adding or exposing more polar groups
Synthetic (phase II) rxns
Conjugation
- Inactivates almost all drugs
- creates highly polar conjugates
First pass effect
All tissues can metabolize drugs, but the liver is the biggie.
- PO drugs pass through liver first and are metabolized, thus oral formulae must have a higher dose.
Cytochrome P450
Known as a mixed function enzyme
- drugs must be lipid soluble to reach these enzymes
- most phase I reactions and phase II glucuronidation result from microsomes activity
Induction of microsomal enzymes
Some drugs induce the activity of these enzymes increasing their metabolism or a drug administered with them.
- greatest effect seen in PTs. With slow activity prior to induction
- enzyme induction takes several days, and recovery like wise.
Common inducers of P450 (P450 is a circus)
Carbamazepine Isoniazid Rifampin (lots of drugs) Chronic alcoholism (Long term tobacco use) St. John's wort
Common inhibitors of P450
Acute ethanol toxicity (GAS will shut down a conversation)
- grapefruit juice
- statins (assoc. with rabdo)
- note: lots of warfarin interactions on both lists…
Variations in drug metabolism among populations
- Poor: 5-10% of European descent (reduced clearance of warfarin leads to significant drug interactions) 1-2% if south East Asians
- intermediate
- extensive
- ultra rapid: 30% Ethiopians/Saudis; reqs a dose up to 3x normal to achieve therapeutic plasma levels.
~ codeine is metabolized to morphine faster resulting in abdominal cramps
Phase II conjugation reaction (passive)
Conjugate center is usually a carb or amine (most commonly glucuronic acid)
- enhances secretion (attaches it to highly hydrophilic molecule)
- results in compound that is more toxic
- methylation is the only conjugation that doesn’t increase hydrophilicity
Phase II conjugation reaction (active)
Metabolites formed are almost always inactive, less soluble, highly ionized and T/F much more likely to be excreted.
- may occur with steroids in the stomach resulting in increased activation time for them.
CYP450 conjugated substrates
- organic acids, OH containing drugs, roid hormones, biliruben
- all others are NON- microsomal metabolized
Kernicterus: cause and trt
Toxic entry of unconjugated biliruben into infant CNS
- infants are hyper reactive to drugs and normal products because UDP- glucuronlyltransferase is not developed
Trt: phototherapy/phenobarbital
Fetal exposure to drugs
- rate of delivery to placenta: lipophilicitiy increases crossing
- chemical properties of drug: size of drug 1000 is sort of the cut off for crossing
- maternal albumin decreases in pregnancy
~ may result in greater free drug -> greater distribution to bebe
Maternal binding affinity: do LAABS before prescribing mom something.
Ampicillin, barbiturates, sulfonamides, local anesthetics bind more to maternal albumins
Salicylates and others bind more to fetal plasma proteins
