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PB+T > Pharmacokinetics-2 > Flashcards

Pharmacokinetics-2 Flashcards

0
Q

Urinary filtration: general

A
  • 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)
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1
Q

Glucuronidation

A

Hydrolyzing drug products in the liver to return to circulation after absorption in the gut via secretion int the bile.

  • morphine
  • digoxin
  • rifampicin
  • PCP
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2
Q

Filtration in the tubule by location

A
  • 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
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3
Q

Organic acid active transport molecule

A

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
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4
Q

Inulin and creatinine

A

Both good approximate of GFR

- not secreted (creatinine is 10-15%) or absorbed

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5
Q

Clearance based on inulin/clearance

A

UV/P

  • (urine [compound])(urine excreted)/[compound at midpoint of collection interval]
  • normal adult ~ 125ml/min
  • most accurate/least practical
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6
Q

Drug Clearance time (125 mL/min men; 100 mL/min women)

A
  • 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)
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7
Q

CrCl (CG formula)

A

(140-age)(weight in kg)(.85 if female)/(72xplasma creatinine)

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8
Q

IBW

A

50kg + 2.3(inches over 5 feet)

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9
Q

Metabolite effect on secretion

A

Metabolites tend to be more polar, thus increasing excretion

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10
Q

Non-synthetic (Phase I rxns)

A

Oxidation
Reduction
Hydrolysis
- inactivates, alters or ignores some drugs
- increases hydrophilicity by adding or exposing more polar groups

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11
Q

Synthetic (phase II) rxns

A

Conjugation

  • Inactivates almost all drugs
  • creates highly polar conjugates
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12
Q

First pass effect

A

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.

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13
Q

Cytochrome P450

A

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
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14
Q

Induction of microsomal enzymes

A

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.
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15
Q

Common inducers of P450 (P450 is a circus)

A 
Carbamazepine 
Isoniazid 
Rifampin (lots of drugs) 
Chronic alcoholism  (Long term tobacco use)
St. John's wort
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16
Q

Common inhibitors of P450

A

Acute ethanol toxicity (GAS will shut down a conversation)

  • grapefruit juice
  • statins (assoc. with rabdo)
  • note: lots of warfarin interactions on both lists…
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17
Q

Variations in drug metabolism among populations

A
  • 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
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18
Q

Phase II conjugation reaction (passive)

A

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
19
Q

Phase II conjugation reaction (active)

A

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.

20
Q

CYP450 conjugated substrates

A
  • organic acids, OH containing drugs, roid hormones, biliruben
  • all others are NON- microsomal metabolized
21
Q

Kernicterus: cause and trt

A

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

22
Q

Fetal exposure to drugs

A
  • 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
23
Q

Maternal binding affinity: do LAABS before prescribing mom something.

A

Ampicillin, barbiturates, sulfonamides, local anesthetics bind more to maternal albumins

Salicylates and others bind more to fetal plasma proteins

24
Q

Total body water trends

A

Decreases as the child ages (premis:85%, adult: 50-60)

25
Q

Children plasma protein binding affinity

A

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
26
Q

Phase II in neonates

A

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.
27
Q

Renal function of neonates

A

Renal function: 35% of adult function t/f drugs dependent in renal clearance have increased active time

28
Q

Renal excretion in the elderly

A
  • 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.
29
Q

Pharmacodynamic changes in the elderly

  • CNS
  • neuro receptors
  • baroreptors
A
  • 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)
30
Q

On-target vs. off target effects

A

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

31
Q

NAPQI

A

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

32
Q

Probenacid

A

Inhibits non-selective (relatively) organic acid/base transporter
( gun to my head, I’d say acid over base)

33
Q

Glutathione metabolism

A

Acetaminophen

34
Q

CYP3A4

CYP2D6

A

Do the lions share of P450 work (75%)

35
Q

Effect of alcohol acutely and chronically on inducing

A

Acute ethanol toxicity: inhibition of enzymes

Chronic ethanol use: inducing of enzymes

36
Q

Acetylation: examples

A

Isoniazid (anti TB)

Commonly other amines

37
Q

Hydrolysis: examples

A

Succinylcholine

38
Q

Grapefruit juice

A
  • Enzyme inhibition: CYP2D3,3A4

- p- GPTN inhibition: furanocumarin

39
Q

Inhibitors of P-gp

A

Furanocumarins, verapamil

P-glyc is a rapper: verapamil

40
Q

CHORE

A

Excretion (greatest to least)

Conjugation, hydrolysis, oxidation, reduction (e for excretion)

41
Q

ASCKI Computer Generated (ASCII is a turnoff: inhibitors of CYP450)

A 
Allopurinol 
Saquanivir
Chloramphenicol 
Ketoconazole
Isoniazid 
Cimetidine 
Grapefruit juice
42
Q

Alcohol dehydrogenase

A

CYP450- independent metabolization

43
Q

GGGSMA are non-inducable phase II

A 
Glutamine
Glycine
Glutathione
Sulfination
Methylation
Acetylation
44
Q

Microsomal enzyme catalyzation

A

Glucuronic acid conjugation
OH
Steroid hormones
Biliruben

45
Q

Passing gas is toxic

A

Glucuronic acid conjugation is generally passive and results in toxic intermediate.

46
Q

Renal secretion of drugs

A

Most are secreted back into blood in the DCT

PB+T (20 decks)

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