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Pharm > Drug Translocation / Biotransformation > Flashcards

Drug Translocation / Biotransformation Flashcards

1
Q

Absorption

A

Translocation of drug across lipid bilayers into vasculature

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2
Q

Distribution

A

Distribution of drug via vasculature and across lipid bilayers from vasculature to drug’s target

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3
Q

Metabolism

A

Biotransformation of drug (primarily by liver)

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4
Q

Elimination

A

Removal of drug from a body (primarily by kidney) (most in urine/feces)

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5
Q

What happens to a drug as it enters the body?

A

Absorption —> distribution to tissue —> biotransformation —> redistribution —> elimination

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6
Q

Drugs that undergo passive diffusion

A

Small
Neutral/non polar
Lipophilic
Large Vd (i.e. in organs/fat, not water)
Not saturable

I.e. alcohol

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7
Q

Drugs that undergo active transport

A

Large
Charged/polar
Hydrophilic
Smaller Vd (distribution into blood)
Uses transporters (saturable)

I.e. NSAIDS

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8
Q

Transporter superfamilies

A

ABC family (P-glycoproteins)
SLC family (solute carriers - i.e. Organic Anion/Cation Trasnporters)

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9
Q

ABC family

A

ATP-binding cassette

Transmembrane effluent pump, moves drugs/metabolites out of cell

REQUIRES ATP

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10
Q

SLC family

A

Solute Carriers

(I.e. OAT, OCT)

Facilitated transporters; use ionic gradients/built in tranmembrane potentials

Does NOT require ATP

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11
Q

Organs with ABC/SLC transporters

A

Intestine
Liver
Kidney
Brain

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12
Q

Function of ABC family transporter in brain

A

Important for pumping chemicals / substances OUT of brain

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13
Q

Mutation of ABCB1 gene in collies

A

Causes ivermectin toxicity - MDR1 deficiency due to early stop codon

Neurotoxicity - inability to pump out of brain

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14
Q

Biotransformation phases

A

Phase I - oxidation

Phase II - conjugation

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15
Q

Most common phase I rxn

A

Oxidation - Cyt P450

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16
Q

Common phase II reactions

A

Glucuronidation / glucosidation
Acetylation

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17
Q

Most metabolic products are

A

Less pharmacologically active

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18
Q

Prodrugs

A

Drugs where metabolite is more active than substance administered

E.g. cefpodoxime proxetil, erythromycin-ethylsuccinate, codeine

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19
Q

Types of oxidation reactions

A
  1. Oxygen incorporated (hydroxylation)
  2. Oxidation causes loss of part of drug (oxidative delaminating, dealkylation)
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20
Q

Oxidative enzymes

A

Mixed function oxidases / monooxgygenases (CYP450)

Flavoprotein (NADPH-CYP450 reductase)

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21
Q

Oxidation by cytochrome P450

A
  1. Oxidized (Fe3+) CYP450 complexes with drug
  2. NADPH donates 2 electrons —> Fe2+ —> oxygen binds
  3. Second electron activates oxygen
  4. Activated oxygen transferred to drug
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22
Q

Biotransformation by CYP450

A

Aliphatic/aromatic hydroxylation
Dealkylation
N-oxidation, S-oxidation
Deamination
Dehalogenation

23
Q

Families of most drug metabolizing CYP450 families

A

CYP 1, 2, 3

Humans - CYP3A4/5 and CYP2D6

24
Q

Significance of diversity of CYP enzymes

A

Many drugs are metabolized by different family’s

Some drugs may be metabolized by multiple family’s —> redundancy

25
Q

Phase II - Conjugation reactions

A

Glucuronidation
Acetylation
Sulfonation
Amino acid conjugation
Glutathione conjugation

26
Q

Reactions catalyzed by UDP-glucuronosyltransferase

A

Glucuronic acid conjugation to…

Phenols, tertiary amines, aromatic amines

27
Q

Metabolism of ibuprofen

A

CYP2C9 and 2C19 hydroxylation at different positions

ALDH1 / ALDH2 carboxylate the drug

Glucuronyl transferase conjugates to glucuronic acid

28
Q

Elimination of ibuprofen

A

15% as parent drug
9% oxidized
17% conjugated

29
Q

Principal site of Phase I/II reactions

A

Liver

30
Q

Supplemental sites of Phase I/II reactions

A

GI, lungs skin, kidneys, brain, heart

31
Q

Enterohepatic recycling

A

Reabsorption of nutrients from liver

Responsible for second peak of absorption

32
Q

Modifications by microbiota

A

Microbiota can deconjugate drugs to facilitate reabsorption

33
Q

Factors affecting drug translocation / biotransformation

A

Species/breed

Within individual:
Age, obesity, hydration status, diet, hepatic disease, renal disease, drug-drug interactions

34
Q

CYP450 activity in greyhounds

A

Lower CYP2B11 activity in greyhounds

Decreased activity + lean body mass (lower Vd for lipophilic drugs) —> slow recovery from anesthetics (because slow metabolism)

35
Q

CYP450 activity in cats

A

Lack CYP2B6 in liver
(Enzyme that metabolizes diazepam)

Diazepam —> hepatic necrosis

36
Q

CYP450 activity in horses

A

Low activity of CYP2D —> monensin toxicity (never given to horses, but possible contamination at feed plant - from ruminant feed)

37
Q

CYP450 activity in micro/mini pigs

A

Increased CYP activity —> need higher doses in general

38
Q

Effects of CYP2D6 polymorphisms

A

Studies in humans

Inactive alleles —> low metabolism
- homozygous carriers —> poor metabolizes (18% population)
- homozygous or WT carriers —> 60-70% population
- multiple copies of CYP2D6 —> ultra rapid metabolizers (10-22%)

39
Q

Metabolized by CYP450 2D6

A

Codeine, beta-blockers, tricyclic antidepressants, estrogen receptor modulators, antihypertensive drugs, SSRI

40
Q

Slow and fast metabolizers have been demonstrated in …

A

Humans and beagles

41
Q

Phase II differences in cats

A

Lack glucoronidation - lack UGT1A6 —> slow clearances of aspirin; toxicity of acetaminophen (by alternate pathway of metabolism - toxic intermediates)

42
Q

Phase II differences in dogs

A

N-acetyltransferase deficiency —> hypersensitivity of sulfonamides, longer HL of hydralazine, procainamide not metabolized to active metabolite (some activity as parent)

Thiopurine methyltransferase (TMT) —> metabolizes azathioprine (immunosuppressant) + active metabolites into inactive metabolites —> activity varies across breeds

43
Q

Phase II differences in pigs

A

Lack sulfate conjugation —> compensate with other Phase II pathways

44
Q

Phase II differences in avian / reptiles

A

Unique amino acid conjugation, unknown clinical relevance

45
Q

Ruminant sensitivity to Xylazine

A

Pharmacodynamic difference

Terminal phase of elimination similar between cows and horses, but lower threshold for conc in cows

Difference accounted for by the way in which the drug interacts with the G protein in cattle - direct results of active site interactions

46
Q

Effect of age on Phase II

A

Vd of polar drugs highest in young animals —> decreases with age

Vd of lipophilic drugs increases with age

In geriatric patients —> decrease in metabolism of drugs —> decrease dose in geriatrics

47
Q

Effect of obesity on Phase II

A

Higher percentage of body fat —> higher Vd for lipophilic drugs —> need higher doses

Drugs that do not distribute to fat may need to be dosed based on optimal body weight!

48
Q

Effect of diet on Phase II

A

Chloride - affects Br absorption (epileptic drugs)

Grapefruit juice - CYP3A4 inhibitor

St John’s wort - CYP3A4 + CYP2D6 inhibitors

49
Q

Effect of dehydration on Phase II reaction

A

Decreases Vd for polar, hydrophilic substances

50
Q

Diseases altering drug metabolism

A

Chronic liver disease
Cardiac disease (reduced hepatic blood flow)
Acute myocardial infarction
Viral/bacterial infection
Intestinal disorders (including cancer)
Autoimmune disease
Chronic kidney disease

51
Q

Impact of CKD on drug metabolism/excretion

A

Dec globular filtration/tubular secretion

Accumulation of uremic toxins —> to intestine —> increased drug bioavailability (down regulate CYPs, down regulate efflux transporters)

Decreased hepatic uptake/metabolism

Increased biliary excretion

52
Q

Three categories of CYP450 inducers

A

Phenobarbital

Polycyclic aromatic hydrocarbons

Glucocorticoids

53
Q

Inhibitors of CYP450

A

Azole family of antifungals (e.g. ketoconazole)

54
Q

Coadministration of Ketoconazole and cyclosporin

A

Ketoconazole inhibits CYP450 + MDR1
(Decreases metabolism of cyclosporin)

reduce amount of cyclosporin needed to administer (decrease expense)

Pharm (10 decks)

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