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Pharmacology > Metabolism > Flashcards

Metabolism Flashcards

1
Q

The lipophilic nature of drugs that allows diffusion across cell mbs & access to their sites of action is also a hindrance, why?

A

It’s a hindrance to their elimination from body (mainly due to reabsorption from kidney tubules back into systemic circulation)

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2
Q

Why is biotransformation of drugs essential?

A

biotransformation (or metabolism) to more water-soluble metabolites is essential to terminate their biological activity & eliminate them from body

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3
Q

What do biotransformation enzymes do?

A

convert lipophilic drugs into highly water-soluble metabolites that are easily excreted from body (mainly in urine & to lesser extent bile/feces)

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4
Q

what is biotransformation?

A

enzyme-catalyzed conversion of 1 xenobiotic into another

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5
Q

for most drugs, their duration of action is inversely proportional to …

A

… the rate at which they are metabolically inactivated

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6
Q

biotransformation of drug is the main determinant of its …

A

… half-life (t 1/2)

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7
Q

How are biotransformation reactions categorized?

A

Either Phase I or Phase II reactions

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8
Q

What is a phase I biotransformation reaction?

A

biotransformation enzymes modify the drug mc mainly by OXIDATION (addition of -OH (hydroxyl) grp to drug)

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9
Q

What is a phase II biotransformation reaction?

A

synthetic reactions that CONJUGATE the drug w/ highly polar endogenous cmpd in cell (ex: carbohydrate, sulphate, or acetate)

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10
Q

How is a drug often biotransformed?

A

Sequentially through both Phase I & II reactions

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11
Q

Where is the most important site for drug biotransformation?

A

Liver

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12
Q

Which tissue has high amts of xenobiotic-metabolizing enzymes?

A

Liver

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13
Q

Which tissues have medium amts of xenobiotic-metabolizing enzymes?

A

lung, kidney, intestine

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14
Q

Which tissues have low amts of xenobiotic-metabolizing enzymes?

A

skin, testes, placenta, adrenals

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15
Q

Which tissue has v. low amts of xenobiotic-metabolizing enzymes?

A

nervous system

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16
Q

What is the important biotransformation reaction in Phase I?

A

Oxidation

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17
Q

What are the important biotransformation reactions in Phase II?

A

Sulphation, glucuronidation, glutathione conjugation, acetylation

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18
Q

What are Cytochrome P450-dependent monooxygenases?

A

(CYPs, aka mixed-fxn oxidases); they are the mjr Phase I oxidative enzymes

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19
Q

where are CYP enzymes located?

A

on smooth endoplasmic reticulum

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20
Q

What do reactions w/ CYP enzymes involve?

A

adding or exposing a polar functional grp (ex: -OH, -COOH, -NH2) to lipophilic drug molecule (catalyze insertion of an oxygen atom into drug mc)
[Rxn: Drug (RH) + O2 + NADPH -> metabolite (ROH) + H2O + NADP+]
(NADPH is electron source)

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21
Q

What other reactions are CYPs involved in other than biotransformation of drugs & other xenobiotics (foreign chemicals)?

A

a wide variety of catabolic & anabolic reactions involving endogenous compounds (ex: steroid hormones)

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22
Q

How many CYP enzymes have been identified and how are they designated?

A

> 100 different CYP enzymes have been identified; designated in families CYP1, CYP2, CYP3 or subfamilies CYP1A, CYP2B, etc. based on DNA sequence similarities

23
Q

Why are CYP enzymes v “versatile” & unique?

A

they have broad & overlapping substrate specificities;
- Broad: 1 enzyme can biotransform many drugs
- Overlapping: 1 drug can be biotransformed by several enzymes

24
Q

CYP enzymes usually inactivate a drug but what else can they do?

A

In certain cases they can BIOACTIVATE a drug to a more pharmacologically or toxicologically active metabolite

25
Q

Biotransformation can result in a metabolite with…

A

greater pharmacological or toxicological activity

26
Q

once multicellular animals evolved a GI tract, this became a …

A

… mjr route of exposure to toxic substances (ex: plant toxins

27
Q

To survive toxic substances, organisms had to…

A

…evolve a strategy to intercept & detoxify potentially lethal substances. This is first pass drug biotransformation.

28
Q

How does first pass drug biotransformation work?

A
  • accomplished by HEPATIC PORTAL VENOUS SYSTEM, which delivers all substances absorbed from gut to liver (w/ its extensive biotransformation capacity) before they reach systemic circulation & are delivered to rest of body (to exert effects)
  • this FIRST-PASS EFFECT can result in nearly complete inactivation (>90%) of certain drugs after oral ingestion
  • for this reason certain drugs are not given orally & are administered via different routes (ex: nitroglycerin given sublingually)
28
Q

What is oral bioavailability?

A

Fraction of an orally administered drug that reaches the systemic circulation in an unchanged form.

28
Q

The first pass effect lowers a drug’s…

A

… degree of bioavailability

29
Q

What is AUC?

A

area under the curve

30
Q

Eqn for oral bioavailability?

A

oral bioavailability = AUC oral / AUC IV

31
Q

What are Phase II biotransformation reactions?

A

Add (conjugate) a large water soluble grp to an existing functional grp on the mc

32
Q

What do Phase II biotransformation reactions majorly increase?

A

water solubility (& thus excretability) of drugs

33
Q

What is the major Phase II biotransformation pathway in mammals?

A

glucaronidation

34
Q

What is the cofactor and enzyme for glucaronidation?

A

enzyme UDP-glucuronosyl transferase (UDP-GT or UGT) & cofactor UDP-glucaronic acid

35
Q

Where is the enzyme UDP-glucuronosyl transferase located? Where are other Phase II enzymes primarily located?

A

On the smooth endoplasmic reticulum membrane. Others are primarily in the cytoplasm.

36
Q

Cofactor and enzyme for sulfation?

A

Sulfotransferase (ST) & cofactor PAPs

37
Q

Cofactor and enzyme for acetylation?

A

enzyme N-acetyltransferase (NAT) & cofactor acetyl coenzyme A

38
Q

Why cant you give acetaminophen to cats?

A

B/c Fe dont have or have greatly reduced expression of the glucuronosyl transferase enzyme which is needed to metabolize it

39
Q

what are reactive electrophiles?

A

reactive oxygen spp & epoxides

40
Q

what is one of our most important defenses against reactive electrophiles?

A

Glutathione conjugation

41
Q

what is the enzyme and cofactor for glutathione conjugation?

A

glutathione S-transferase (GST) and cofactor is glutathione (GSH)

42
Q

Glutathione cofactor is in what high concentration in most cells?

A

mM concentration!

43
Q

how abundant is glutathione S-transferase?

A

abundant; approximately 5% of cytosolic protein in liver cells

44
Q

Talk about acetaminophen biotransformation:

A
  • Acetaminophen is active ingredient in tylenol
  • it can go through sulfation or glucuronidation and these are happy pathways
  • however, it can also be activated by a cytochrome P450 to N-acetyl-p-benzoquinoneimine (or N-acetyl-benzosemiquinoneimine) which wants an electron
  • it will often get an electron from our bestie glutathione (glutathione conjugation)
  • if not it can bind to hepatic prots leading to centrilobular necrosis (or to renal proteins w/ damage to kidney medulla) which can cause death by liver failure w/in 24 hours
45
Q

What are the genetic and environmental factors that influence biotransformation?

A
  1. enzyme induction & inhibition
  2. intraspecific differences
  3. interspecific differences
  4. sex & age
  5. diet (nutritional factors)
  6. disease (underlying pathology)
46
Q

How does enzyme induction & inhibition influence biotransformation?

A
  • CYP enzymes & phase II enzymes can all be induced (increased activity) & inhibited (decreased activity)
  • v clinically relevant w/ respect to duration of drug action & drug interactions
  • depletion of cofactors (ex: glutathione) can also be v important
47
Q

How do intraspecific differences influence biotransformation?

A
  • genetic differences (polymorphisms) in expression of enzymes
  • can result in subset of pop being “poor metabolizers” or even “rapid metabolizers”
  • classic ex is alcohol dehydrogenase (ADH) in humans
48
Q

How do interspecific differences influence biotransformation?

A
  • recall: hexobarbital sleeping time after same dose
  • cats are poor glucuronidators (UDP-GT), dogs are poor acetylators (NAT), & pigs are poor sulfators (ST)
49
Q

How do sex & age influence biotransformation?

A
  • sex-specific differences in certain CYP enzymes
  • in general, v young & old individuals have lower enzyme activities
50
Q

How does diet influence biotransformation?

A
  • certain dietary ingredients can induce or inhibit phase I or phase II enzymes (ex: grapefruit juice inhibits CYP3A4 in humans)
51
Q

How does disease influence biotransformation?

A
  • impaired liver (or kidney) function can decrease biotransformation (or excretion) of drugs

Pharmacology (14 decks)

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