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23 spring: pharm > Test 2: lecture 5-6 > Flashcards

Test 2: lecture 5-6 Flashcards

1
Q

ADME

A

absorption
distribution
metabolism
elimination

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2
Q

F stands for

A

Bioavailability

absorption: translocation of drug across lipid bilayers into the vasculature

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3
Q

translocation of drug across lipid bilayers into the vasculature

A

absorption

F=bioavilability

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4
Q

distribution of the drug via vasculature and across lipid bilayers from the vasculature to the drug’s target (ie. into the tissues to its target)

A

Vd= volume of distribution

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5
Q

hepatic clearance

A

metabolism of a drug by the liver

CLH

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6
Q

drugs can be eliminated in

A

bile, urine, feces, sweat and breath

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7
Q

what do you need for passive diffusion

A

– Small
– Neutral and Nonpolar
– Lipophilic
– large Vd (> 0.6 L/kg)
– Process is not saturable

– Eg. Alcohol, many anesthetics

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8
Q

what do you need for active transport of drugs

A
  • Large
  • Charged or Polar
  • Hydrophilic
  • smaller Vd (≤ 0.6 L/kg)
  • Process uses transporters and is saturable
  • Eg. NSAIDs
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9
Q

the Vd of passive or active transport will be larger?

A

passive
≥ 0.6 L/kg

means drug will move from plasma into tissues

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10
Q

what is the ABC family of transporters stand for?

A

ATP- binding cassette

P-glycoproteins

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11
Q

where can you find ABC family transporters?

A

protected spaces:
– GI – Gonads – Kidneys – Biliary system – Brain – Placenta

ATP-binding cassette = ATP dependent
aka P-glycoproteins

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12
Q

SLC superfamily of transporters stands for —

A

solute carriers

made of Organic Anion Transporters (OAT) and Organic Cation Transporters (OCT)

ion channels

do NOT require ATP

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13
Q

— and — are types of SLC family transports

A

Organic Anion Transporters (OAT) and
Organic Cation Transporters (OCT)

solute carriers: no ATP needed, facilitated transporters and second active transporters

  • Use ionic gradients or built in transmembrane potentials
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14
Q

SLC family transportes are — transporters and — transporters

  • Use — gradients or built in transmembrane potentials
A

facilitated
second active

ionic

Do NOT need ATP
solute carriers: OAT and OCT

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15
Q

where can you find SLC superfamily transporters

A

everywhere

do not need ATP

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16
Q

what direction does ABC and SLC transporters in the brain work?

A

will pump drugs out of the brain

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17
Q

white footed collies will have — mutation that leads to — toxicity

A

ABCB1= MDR1 deficiency

ivermectin (heartgard)

causes neurotoxicity at high doses

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18
Q

phase I biotransformation reactions are —- reactions

A

oxidation- cytochrome P450

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19
Q

two phase II biotransformation reactions

A

conjugation:

glucuronidation
acetylation

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20
Q

what is a prodrug?

A

drug that needs to be broken down to be activated

the metabolite is MORE active than the substance administered

Cefpodoxime proxetil (aka Simplicef = 3rd generation cephalosporin antibiotic)

Erythromycin-ethylsuccinate (macrolide antibiotic)

Codeine

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21
Q

— are prodrugs

A

Cefpodoxime proxetil (aka Simplicef = 3rd generation cephalosporin antibiotic)

Erythromycin-ethylsuccinate (macrolide antibiotic)

Codeine

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22
Q

Most metabolic products are pharmacologically LESS active

what are three exceptions?

A

prodrugs (codeine)
toxic metabolites (acetaminophen)
carcinogenic metabolites (polycyclic aromatic hydrocarbons)

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23
Q

two type of oxidation reactions

A

hydroxylation

oxidative deamination, dealkylation

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24
Q

— is an oxidation reaction where Oxygen is incorporated into the drug molecule

A

hydroxylation

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25
Q

— is a oxidation reaction where Oxidation causes the loss of part of the drug molecule

A

oxidative deamination, dealkylation

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26
Q

— aka NADPH-cytochrome P450 reductase

A

Flavoprotein

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27
Q

how does oxidation via cytochrome P450 work

A

Oxidized (Fe3+ aka ferric form of heme) cytochrome P-450 combines with a drug substrate to form a binary complex.

NADPH donates two electrons to cytochrome P-450 reductase. One of these electrons reduces the Fe3-cytochrome P-450-drug complex to Fe2+ (ferrous form) The reduced heme P450-drug complex binds O2.

The second electron from P450 reductase serves to reduce molecular oxygen and form an “activated oxygen”-cytochrome P-450-substrate complex.

This complex in turn transfers “activated” oxygen to the drug substrate to form the oxidized product. The potent oxidizing properties of this activated oxygen permit oxidation of a large number of substrates. The second activated O atom is used to form H2O.

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28
Q

oxidation via cytochrome P450

NADPH + H + O2 + drug=

A

NADP^+ + H20 + oxidized drug

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29
Q

phase II Glucuronidation by UDP-Glucuronosyltransferase can be added to

A

-OH, -COOH, -NH2, -SH groups

phenols, 3°-amines, aromatic amines

conjugation reaction

30
Q

phase II Acetylation by acetyltransferase can be added to —

A

on -NH2, -SO2NH2, -OH groups

31
Q

what happens during acetylation

A

actyl CoA is added to something

NAT enzyme is found in many tissues, including liver

can be added to procainamide, histamine and isonizaid

32
Q

where does phase I and phase II reactions take place?

A

liver

Other sites include the GI, lungs, skin, kidneys,
brain, heart

33
Q

what is enterohepatic recycling

A

drugs in the liver → bile → excreted into the GI tract, can become activated, or reabsorbed or metabolized (recycles)

34
Q

ATP requiring — family pumps for efflux.

— exchangers required for drug absorption from intestine or blood by tissues and in some cases protein carriers.

A

ABC= ATP-binding cassette= P-glycoproteins

SLC family (solute carrier)

35
Q

Phase I drug metabolizing enzymes: — enzymes (mixed function oxidases); Flavin Mono oxygenases; Monoamine oxidases, Alcohol/Aldehyde dehydrogenases.

A

Cytochrome P450

36
Q

Phase II drug metabolism enzymes: — and —, Sulfotransferase, Amino Acid Conjugation, Glutathione-S-transferase

A

UDP-Glucuronosyltransferase

acetyltransferase

37
Q

what are some factors affecting drug translocation and biotransformation

A

Species and Breed Differences

Within an Individual
– Age
– Obesity
– Hydration Status
– Diet
– Hepatic Disease
– Renal Disease
– Drug-drug Interactions

38
Q

Greyhounds have lower CYP2B11 activity than other dog breeds.

this means

A

lower Vd for lipophilic drug= very slow removal and recovery

do not do well with anesthetics (propofol, thiopental)

39
Q

greyhounds do not do well with anesthetics (propofol, thiopental) because —

A

lower CYP2B11 activity

lower Vd of lipophilic drugs because of decrease enzyme activity and low body fat

40
Q

cats don’t have CYP2B6 in the — which leads to

A

liver

hepatic necrosis if you give them diazepam

41
Q

— leads to monensin toxicity in horses

A

low CYP2D

phase 1 CYP240 difference

42
Q

why do micro pigs need higher doses of drugs?

A

increased activity of CYP

phase I CYP450

43
Q

there are changes within a species for CYP2D6

— will make you a poor metabolizer

A

Homozygous carriers (Ex4/4)

(~18% of population)

44
Q

there are changes within a species for CYP2D6
— will make a normal metabolizer

A

Homozygous (Ex 1/1) or WT/WT

(60-70% of population)

45
Q

there are changes within a species for CYP2D6

— will make you a rapid metabolizer

A

multiple copies (2-3)
(~10-22% population)

46
Q

should you increase or decrease the dose for poor metabolizers for codeine?

A

active form is morphine

if poor met- need more of drug to get same effect

if ultra met- need less of drug to get same effect

47
Q

Poor metabolizers of codeine will have — pharmacological effect at normal dose while Ultra metabolizers will have — level of active compound potentially causing drug toxicity

A

poor

higher than normal

48
Q

The canine — is inhibited by fucocumarins (present in grape fruit juice and a other citrus fruits and veggie products), and St. John’s Wort.

A

CYP3A12

49
Q

cats have slow aspirin clearance and acetominophen toxicity because —

A

lack glucoronidation

(UGT1A6 = uridine diphosphate glucuronosyl transferase)

50
Q

Dogs have N-acetyltransferase deficiency → can’t efficiently metabolize — resulting in hypersensitivity

A

sulfonamides

51
Q

dogs have — deficiency where Hydralazine (vasodilator) has a much longer halflife than humans

A

N-acetyltransferase deficiency

11 to 13 h instead of 2 to 4 h

phase II difference

52
Q

dogs have variations in — which metabolizes azathioprine (immunosuppressant) and active metabolites into inactive metabolites. which dogs have the highest and lowest?

A

Thiopurine methyltransferase (TMT)

Giant Schnazuers had lowest activity (need lower dose)
Alaskan malamutes had high activity (need higher dose)

53
Q

Avian and Reptiles: unique amino acid conjugation - benzoic acid is conjugated to ornithine instead of —

A

glycine

phase II differences

54
Q

Dogs with N-acetyltransferase deficiency: — is not metabolized into the active metabolite (NAPA), however it is still effective

A

procainamide

phase II differences

55
Q

what deficiency leads to dogs not metabolizing sulfonamides?

A

N-acetyltransferase deficiency

  • procainamide is not metabolized into the active metabolite (NAPA), however it is still effective
  • Hydralazine (vasodilator) has a much longer halflife than humans; 11 to 13 h instead of 2 to 4 h
56
Q

what happens to xyalzine binding in cows

A

⍺2 receptors

G protein acts in different way when binded to xyalzine

difference in pharmodynamics (drug interacting with receptor)

57
Q

Vd of polar water soluble drugs is — in young animals and — with age eg. gentamicin (antibiotic) dose is — for “juvenile” animals compared with “adult” animals

A

highest

decreases

higher

young animals have more water= more movement of water soluble drugs out of plasma into water

58
Q

Vd for — drugs tends to increase with age due to increased % body fat

A

nonpolar lipophilic

older people are fat

59
Q

high percentage of body fat increases the Vd for lipophilic drugs, requiring higher doses to be administered for the same effect; drugs that do not distribute to fat may need to be dosed based on — to avoid toxicity

A

optimal body weight

60
Q

as Cl increases, — absorption decreases and vice versa

A

bromide

61
Q

— juice - CYP 3A4 in humans/CYP3A12 in dogs inhibitor; highly variable effects; fucocoumarins

A

Grapefruit

62
Q

St John’s wort, other herbal products – Inhibits —

A

CYP3A4 in humans= CYP3A12 in dogs
CYP2D6 in humans = CYP2D15 in dogs (poor met, normal, ultra met)

63
Q

Dehydration decreases Vd for — substances

A

polar, hydrophilic

64
Q

what kind of disease can alter drug metabolism and transport

A

liver disease
cardiac (decreased blood flow)
viral/bacterial infection (fever= increased met)
cancers
autoimmune disease
CKD

65
Q

CKD produces uremic toxins which can downregulate — and —

A

CYPs
efflux transporters (P-gp, MRP)

causes increased bioavilablility

66
Q

CKD leads to decreased excretion by the liver, which goes to the liver and —

A

transporters are downregulated

leads to more drug getting past liver into regulation

also causes increased biliary excretion

need to decrease dose cause not being excreted and more is getting to circulation

67
Q

three major categories of CYP inducers

A
  • Phenobarbital is prototype of one group - enhances metabolism of wide variety of substrates (including its
    own) by causing proliferation of SER
    and CYP in liver cells.
  • Polycylic aromatic hydrocarbons are second type of inducer (eg. benzo[a]pyrene).
  • Glucocorticoids (eg. Dexamethasone)
68
Q

— family of antifungals inhibit CYP450

A

azole (ketoconazole)

69
Q

— is prototype of one group - enhances metabolism of wide variety of substrates (including its own) by causing proliferation of SER and CYP in liver cells.

A

Phenobarbital

induce CYP450

70
Q

Ketoconazole inhibits —

A

CYP450 and MDR1 (P-glycoprotein)

used to decrease metabolism of Cyclosporin

71
Q

— inhibits CYP450 and MDR1 (P-glycoprotein). This antifungal is used to decrease metabolism of —

A

ketoconazole

Cyclosporin (by 75%)

72
Q

use of ketoconazole with cyclosporin can — dose of cyclosporine by as much as 75%!

A

decrease

keto is CYP450 inhibitor- stops breakdown of cyclosporin which is very $$$ and normally breaks down quickly because it is a CYP450 inducer

23 spring: pharm (46 decks)

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