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
Total body water trends
Decreases as the child ages (premis:85%, adult: 50-60)
Children plasma protein binding affinity
Neonates < children < adults
- results in lower levels of toxicity local anesthetics, diazepam, phenytoin, amp, and phenobarbital
- fetal/neonatal albumin has a lower binding affinity for drugs, may be due to altered pH
Phase II in neonates
Not all are absent/underdeveloped at birth
- methylation can occur, however N-demethylation of theophylline is reduced
- glucuronidation is slow (grey baby syndrome: chloramphenicol)
- acetaminophen is normally glucruonidated, but in neonates sulfination occurs.
Renal function of neonates
Renal function: 35% of adult function t/f drugs dependent in renal clearance have increased active time
Renal excretion in the elderly
- GFR decreases 30%
- Renal blood flow decreases
- creatinine clearance decreases 1% per year after age 20
- drug dosage should be decreased in PTs. Over 70 in proportion to their decrease in CrCl.
Pharmacodynamic changes in the elderly
- CNS
- neuro receptors
- baroreptors
- Decreased density of muscarinic/opioid and DA receptors
- decreased B2 affinity
- pre/post synaptic receptor regulation is all squiffy
- reduces B1 receptor responsiveness
- all cAMP decreased in response to B agonists
- reduced baroreceptors sensitivity (reqs a bigger change to flip)
On-target vs. off target effects
On-target effects: drug binds to receptor for which it was intended (right receptor, right tissue)
Off target effect: drug receptor mismatch (right receptor wrong tissue, wrong receptor)
- dose dependent, margin of safety, patient factors
NAPQI
Toxic metabolites result from acetaminophen. Detoxed by CYP450, but when it’s saturated it builds up.
- N-acetylcystine (glutathione precursor) is the antidote. Can’t administer glutathione because
Probenacid
Inhibits non-selective (relatively) organic acid/base transporter
( gun to my head, I’d say acid over base)
Glutathione metabolism
Acetaminophen
CYP3A4
CYP2D6
Do the lions share of P450 work (75%)
Effect of alcohol acutely and chronically on inducing
Acute ethanol toxicity: inhibition of enzymes
Chronic ethanol use: inducing of enzymes
Acetylation: examples
Isoniazid (anti TB)
Commonly other amines
Hydrolysis: examples
Succinylcholine
Grapefruit juice
- Enzyme inhibition: CYP2D3,3A4
- p- GPTN inhibition: furanocumarin
Inhibitors of P-gp
Furanocumarins, verapamil
P-glyc is a rapper: verapamil
CHORE
Excretion (greatest to least)
Conjugation, hydrolysis, oxidation, reduction (e for excretion)
ASCKI Computer Generated (ASCII is a turnoff: inhibitors of CYP450)
Allopurinol Saquanivir Chloramphenicol Ketoconazole Isoniazid Cimetidine Grapefruit juice
Alcohol dehydrogenase
CYP450- independent metabolization
GGGSMA are non-inducable phase II
Glutamine Glycine Glutathione Sulfination Methylation Acetylation
Microsomal enzyme catalyzation
Glucuronic acid conjugation
OH
Steroid hormones
Biliruben
Passing gas is toxic
Glucuronic acid conjugation is generally passive and results in toxic intermediate.
Renal secretion of drugs
Most are secreted back into blood in the DCT
