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Med Chem Test 4 > Drug Metabolism Factors > Flashcards

Drug Metabolism Factors Flashcards

1
Q

What are the pharmacodynamics internal factors that affect drug metabolism?

A

Dose (overdosing)
Route of administration
Distribution (protein/tissue)

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2
Q

What are the physiological internal factors?

A 
Tissue DME's 
Disease
Age
Gender
Genetics
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3
Q

What are the external or environmental factors that affect drug metabolism?

A

Nutritional Status

Induction/Inhibition of drug metabolism enzymes.

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4
Q

How can dose affect drug metabolism?

A

Overdosing can overwhelm DMEs capacities and toxicity can ensue.

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5
Q

What is an example of toxicity caused by overdosing?

A

APAP toxicity.

Glucuronidation and Sulfation are overwhelmed and thus CYP450 creates N-Acetylparabenzoquinoeimine (NAPQ1)

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6
Q

What are the different routes of administration?

A

Instillation, aerosol, oral(inhaler), sublingual, transdermal patch, topical, intramuscular, ear instillation, subcutaneous, intravenous, and suppository.

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7
Q

Oral route is susceptible to what?

A

1st pass effect

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8
Q

What is the 1st pass effect?

A

Pre-systemic metabolism.

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9
Q

Where does the 1st pass effect occur?

A

Gut wall; small intestine (bacterial enzymes); liver; lung.q

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10
Q

What are examples of drugs with significant 1st pass effect?

A

Isoproterenol, lidocaine, nitroglyercin.

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11
Q

How is isoproterenol affected by the 1st pass effect?

A

Intestinal wall Sulfation.

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12
Q

How is lidocaine affected by the 1st pass effect?

A

Ineffective by mouth

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13
Q

How is nitroglyercin affected by the 1st pass effect?

A

It can only be administered buccally.

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14
Q

What factors affect distribution?

A

Serum protein binding, tissue binding, and transporters.

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15
Q

In serum protein binding the bound drug is active or inactive?

A

Inactive

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16
Q

When binding sites are saturated what happens to the free drug?

A

There is more of it.

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17
Q

What does the amount of free drug affect?

A

pharmacological effects and elimination

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18
Q

Protein binding ______ metabolism and _______drug half life.

A

Protein binding decreases metabolism and increases drug half life.

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19
Q

What are examples of drugs that bind to serum proteins?

A

Warfarin, NSAIDs, Sulfonamides; Sulfonylureas; Depakene; Nifedipine; Prazosin; Diphenhydramine

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20
Q

Weak acids bind to what serum protein?

A

albumin

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21
Q

Weak bases bind to what serum protein?

A

alpha-1 acid glycoproteins

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22
Q

What are other serum binding proteins?

A

lipoproteins, globulins (alpha, beta, and gamma)

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23
Q

What does tissue drug binding involve?

A

Non-specific binding to proteins and lipids.

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24
Q

Tissue binding increases what?

A

Drug concentration in tissue.

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25
ABC transporters determine what?
oral bioavailability cellular accumulation excretion
26
What are the transporter proteins?
usually influx/efflux transporters.
27
What tissue specific enzymes are expressed in the skeletal muscle?
CYP2C9, MAO-A, MAO-B
28
What tissues are the MAO-A AND THE MAO-B not expressed in?
the skin
29
What enzymes are expressed in almost every tissue except skeletal muscle?
CYP2D6 CYP2E1 CYP3A4 CYP3A5
30
What disease states effect drug metabolism?
Liver diseases, Cardiac diseases, diabetes, inflammation/infection, thyroid disease
31
How does liver disease effect drug metabolism?
decreases it
32
How does cardiac disease affect drug metabolism?
decreases it due to reduced liver blood flow
33
How does diabetes affect drug metabolism?
???
34
How does inflammation/infection affect drug metabolism?
decreases it
35
How does thyroid disease affect drug metabolism?
increases protein synthesis in hyperthoidism and therefore has elevated drug metabolism enzyme activity.
36
For acute/chronic liver disease the effects on drug metabolism are...
not always predictable but if a drug must be metabolized by the liver before elimination it will have an effect. Toxicity due to over dose is common.
37
Why does age impact drug metabolism?
Hepatic plus-hepatic enzyme maturation (some fetal hepatic enzymes disappear or decrease after birth and some appear right after birth or later in life) hepatic blood flow liver weight
38
What enzyme has a late appearance in life?
CYP1A2
39
When do CYP450s form in the fetus?
Earlier in gestation then Phase II
40
What are common drug metabolism enzymes in the fetus?
CYP1A CYP3A7 SULTs
41
Is phase 1 or 2 more common in drug metabolism in a fetus?
Phase 1
42
Are fetuses more or less susceptible to toxicity?
More
43
What enzymes do neonates have a low concentration of?
UGT | They have inadequate (UGT1A1) conjugation of bilirubin which leads to jaundice or hyperbilirubinemia.
44
What drugs should you avoid with neonate?
Ones that require Glucuronidation for elimination.
45
What drugs may cause gray baby syndrome?
Chloramphenicol and omeprazole because of the inability to conjugate due to the high SULTS capacity.
46
How does age affect drug metabolism?
Changed body mass/composition. Overall slow metabolic activity Susceptible to toxicity
47
How does the changed body mass/composition affect drug metabolism?
Less metabolic activity (Less metabolic activity) | Alterations to pharmacokinetics (less excretion, less liver blood flow, less renal filtration rates)
48
Sex hormones stimulate the release of what?
GH by pituitary gland
49
GH are release less frequently in males or females?
males Androgens increase metabolism Estrogen decreases metabolism
50
What are some drugs that sex differences affect?
Nicotine, Aspirin, Alcohol, Propranolol, diazepam, etc...
51
How do stress hormones affect DM?
Increased glucocorticoid levels induce DME expression.
52
How does pregnancy affect DME?
Increased sex hormones, fetus metabolic activity, increased plasma volume, increased liver blood flow, increased glomerular filtration, increased 2D6, increased 3A4, increased UGT
53
What enzymes have DME Polymorphism?
CYP2A6, 2C9, 2C19, 2D6
54
CYP2D6 can be what?
Poor metabolizers, PM Intermediate metabolizers, IM Ultra-rapid Metabolizers, UM Extensive Metabolizers, EM
55
Which population has ALDH polymorphisms?
Japanese and Chinese have a flushing response due to inactive hepatic ALDH1
56
What population has NAT polymorphisms?
Caucasians with slow acetylators and rapid acetylators
57
What population has CYP2C19?
20 percent of Asians | 3 percent of Caucasians
58
EM and PM DME phenotypes are similar to Drug Induction and Inhibition, respectively. T/F
True
59
Cats have _____ but lack ____ and vice versa for Pigs?
SULTs | UGTs
60
Humans have _____ CYP2D isoform but ______ have six.
one | rats
61
How does nutritional status affect drug metabolism?
Carbohydrate impact is mixed Decreased lipid and protein intact can decrease microsomal drug metabolizing activity. Lead to slow and erratic GI absorption. Vitamins and minerals may be needed in Phase 1 oxidations. Malnutrition may decrease clearance and increase toxicity.
62
What drugs causes a reduced or delay by food?
Reduced or delayed. Ex: Ampicillin, Aspirin, Atneolol, Azithromycin, Captopril; Cefaclor; Cefixime; Cephalexin.
63
What drugs increase absorption with food?
Ketoconazole, lithium, lovastatin, metoprolol, nitrofurantoin, propranolol, propoxyphene
64
What are PAHs and how do they affect drug metabolism?
smoked foods, cigarettes smoke, etc. Increase CYP1A2 activity. CYP1A2 convers PAHs into carcinogens implicated in lung/colon cancers...slow process.
65
Where do indoles come from and what do they do?
They come from vegetables (cabbage). | Upregulate CYP1A
66
Where do Isothyocyanates come from and what do they do?
Come from vegetables (watercress) | Inhibit CYP2E1
67
Where do Oragnosulfur compounds come from and what do they do?
Come from garlic Inhibit CYP2E1 Induce CYP1A, CYP3A and Phase II enzymes
68
What does grape fruit juice do?
Decreases CYP3A activity.
69
Where does Tyramine come from and what does it do?
Smoked, aged or pickled meat/fish/sauerkraut/cheesed, etc | High tyramine blood levels can disrupt endogenous catecholamine metabolism. Outcome: fatal hypertension.
70
What are factors that induce or inhibit drug metabolism enzymes?
Exposure to... DME inducing/inhibiting drugs contaminants/pollutants in air, food, and water non-contaminants in air, food (preservatives), and water
71
Enzyme induction does what to enzymatic levels and activity?
Increases
72
Enzyme induction does what to transcription and translation?
increases
73
Enzyme induction does what to protein degradation?
Decreases
74
Generally, induction does what to... DME activity drug blood levels Duration of action
DME activity increases drug blood levels decrease Duration of action decreases
75
What are common inducing agents?
``` Nevirapine Efavirenz Ritonavir Rifampin Rifabutin Phenobarbital Carbamazepine Phenytoin Ehtanol St. John's Wort ```
76
What is Cyclosporin A and what happens when 3A4 is induced?
Cyclosporin A is an immunosuppressant. It requires 3A4 for its metabolism so when it is induced it causes drug inactivation of Cyclosporin A and thus causes transplant failure.
77
What are some examples of Polycyclic Aromatic Hydrocarbons (PAHs)?
Napthalene, Acenaphtlene, Anthracene, 1,6-Dimethylnapthalene, Fluorene, 1-Methylanthracene, Biphenyl, Phenathrene, 9,10-Dimethylanthracene (they all have 2 or more cyclic rings.
78
What to dioxins and PCBs do?
Induce enzymes. They look like cyclic rings with Cl's on them.
79
How long does reversible enzyme inhibition last?
2-3 days
80
How long does irreversible enzyme inhibition last?
Drug is bound to enzyme for a longer period Drug or Intermediate or Metabolite complexation with DME New enzyme has to be formed.
81
What occurs in mechanism-based inactivation of DMEs?
Reactive metabolite formed binds to DME and inhibits its activity. They are called suicide substrates.
82
DME inhibition does what to... Drug activity or toxicity Drug blood levels duration of action
Increases drug activity or toxicity Increases drug blood levels Increases duration of action
83
DME inhibition effects are greater on the liver enzymes or GI enzymes?
The effects are greater on the GI enzymes.
84
What are the inhibitors of drug metabolism?
``` Protease inhibitors Delavirdine Efavirenz Fluconazole Itraconazole Ketoconazole Voriconazole Isoniazid Ciprofloxacin Grapefruit Juice Clarithromycin Erythromycin Diltiazem Verapamil Amiodarone Cimetidine Omeprazole Fluoxetine ```
85
What causes grape fruit juice to inhibit DME?
Furocoumarins - mechanism based inhibitors of 3A4
86
What are some potential outcomes of DDIs?
Hemorrhage, Hypoglycemia, Immunosupression, CNS depression
87
What factors contribute to drug response variability?
Internal & external factors Genetic Differences in DMEs DME induction/inhibition (lead to DM related DDIs, Inducers usually increase clearance, Inhibitors usually diminish clearance).
88
What are the internal and external factors?
Internal - Dose, Route of administration, Distribution, Nutrition, Disease, Age, Gender & Hormones, Genetics. External - Exposure to xenobiotics (Inducer/Inhibitor), Diet or food.

Med Chem Test 4 (6 decks)

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