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Pharmacology > BIOTRANSFORMATION > Flashcards

BIOTRANSFORMATION Flashcards

1
Q

WHY DRUG TRANSFORMATION NECESSARY?

A

• Pharmacologically active organic molecules tend to
be lipophilic and they remain unionized or only
partially ionized at physiologic pH; these are readily
reabsorbed from the glomerular filtrate in the
nephron.
• Certain lipophilic compounds are often strongly
bound to plasma proteins and may not be readily
filtered at the glomerulus.
• Metabolic products are often less
pharmacodynamically active than the parent drug
and may even be inactive.
• However, some biotransformation products have
enhanced activity or toxic properties.
• Therefore, lipid-soluble agents are first metabolized
into more polar (hydrophilic) substances in the liver
via two general sets of reactions, called phase 1
and phase 2.

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2
Q

Phase 1 reactions

A

usually convert the parent drug to
a more polar metabolite by introducing or
unmasking a functional group (–OH, –NH2, –SH)

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3
Q

If phase 1 metabolites are sufficiently polar

A

they may be readily excreted.

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4
Q

However, many phase 1 products are not eliminated
rapidly and undergo a subsequent reaction in which
an endogenous substrate such as

A

glucuronic acid,
sulfuric acid, acetic acid, or an amino acid combines
with the newly incorporated functional group to form
a highly polar conjugate.

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5
Q

hydrazide moiety of isoniazid is

known to form an

A

N-acetyl conjugate in a phase 2

reaction

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6
Q

Thus, phase 2 reactions may actually precede

A

phase 1 reactions.

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7
Q

Phase 2 reaction,

A

this facilitates elimination of the

drug and it can be in the form of conjugation, sulfation, acetylation or methylation.

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8
Q

• Phase 1 involves

A

Oxidation-Reduction (REDOX

Reaction)

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9
Q

Phase 2 involves

A

transferases or conjugation

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10
Q

This conjugation reaction usually requires the
substrate to have Oxygen, Nitrogen or Sulfur that
serve as acceptor sites for the hydrophilic moiety,
such as glutathione, glucuronic acid, sulfate or
acetyl

A

: a drug may undergo Phase 1 via
oxidation, addition of Oxygen. And that Oxygen
would serve as a substrate, where in this component
would be added in replace to the functional group.

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11
Q

What is the importance of biotransformation?

A

For elimination

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12
Q

What will happen if the drug is not metabolized?

A

Increase risk for toxicity because the drug
remains in the blood. So, after absorption, it will
be distributed and then metabolize for it to be
excreted.

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13
Q

Phenytoin is highly lipophilic, via Phase 1 reaction

acted upon by

A

CYT p450

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14
Q

Phenoytin Reaction

A

converted, and then addition of a functional
group, forming 4-hydroxy-phenytoin. Then after
Phase 1, this phenytoin would be slightly soluble in
water. It would further undergo Phase 2 reaction by
glucuronidation, addition of UGT, where in your
hydroxyl group serves as the substrate. This
metabolite is more water soluble and it can be easily
excreted in the kidney

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15
Q

WHERE DO DRUG BIOTRANSFORMATION

OCCUR?

A

Liver is the principal organ of drug

metabolism.

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16
Q

If phase 1 metabolites are sufficiently polar

A

they

may be readily excreted.

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17
Q

The small intestine plays an important role in metabolism since drug that are orally administered absorbed by the GUT and taken to the liver through
the portal vein

A

FPM

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18
Q

xenobiotic metabolizing enzyme

A

located
in the epithelial cells of the GI are also responsible
for the initial metabolic process of most oral
medication. So, this should be consider as the initial
site of drug metabolism

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19
Q

Drugs that undergo Substantial FPM

A 
Asprin
Glyceral Trinitrate
Isosorbide dinitrate
Levodopa
Lidocaine
Metoprolol
Morphine
Propanolol
Salbutamol
Verapmil
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20
Q

are more extensively

metabolized in the intestine than in the liver

A

clonazepam, chlorpromazine, cyclosporine

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21
Q 
undergo significant (~50%)
intestinal metabolism.
A

midazolam

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22
Q

First-pass effects may limit the bioavailability of
orally administered drugs (eg., lidocaine) so greatly
that

A

alternative routes of administration must be used to achieve therapeutically effective blood levels.

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23
Q

Furthermore, the lower gut harbors intestinal microorganisms that are capable of many

A

biotransformation reactions

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24
Q

Drugs may be metabolized by gastric acid

A

Penicillin

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25
Q

Digestive enzumes metabolism

A

Polypeptides like insulin

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26
Q

enzymes in the wall of the

intestine

A

sympathomimetic catecholamines

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27
Q

RER are used for

A

protein

synthesis

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28
Q

SER are rich in

enzymes responsible for

A

oxidative drug
metabolism and this is where your Cytochrome P450
enzyme or your mixed function oxidases are located.

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29
Q

PHASE 1 REACTIONS

A

: Oxygenase, addition of
functional group, they can be accomplished by
Cytochrome P450, FMO as well as epoxide
hydroxylases.

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30
Q

phase 1 reaction are three enzymes

A

CytP450

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31
Q

In this oxidation reaction process, 2 microsomal

enzymes play a key role

A

First is your NADPH
(nicotinamide adenine dinucleotide phosphate
dehydrogenase) and 1 mole of this enzyme donates
an electron to the flavoprotein P450 reductase.
(contains 1 mole of FMN/Flavin mononucleotide and
FAD/Flavin adenine dinucleotide).

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32
Q

The second microsomal enzyme is a hemoprotein

called your Cytochrome P450

A

which serves as your
terminal oxidase. So, in its reduced form, in ferrous
form (Fe²⁺) it binds carbon monoxide to give a
complex that absorb light at approximately at 450nm.
Hence, the name Cytochrome P450.

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33
Q

Nomenclature:

A

o The family name is indicated by the Arabic
number that follows CYP, and the capital
letter designates the subfamily, for example, CYP3A
o A second number indicates the specific
isozyme, as in CYP3A4

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34
Q

CYP3A4

A

Responsible for the metabolism of over 50% of the prescription drugs metabolized by the liver.

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35
Q

most common

drugs are

A

CYP1A2, 2A6, 2B6, 2C9, 2D6, 2E1,

3A4.

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36
Q

g efficacy
and there is adverse effect. For example, CYP2D6
has mentioned to exhibit

A

. So, if
the is genetic polymorphism, the risk for drug-drug
interaction also increases.

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37
Q

PHASE 1 REACTIONS: CYTOCHROME P450 (CYP)

ENZYME INDUCTION

A

This results in increased biotransformation of drugs
and can lead to significant decreases in plasma
concentrations of drugs metabolized by these CYP
isozymes, with concurrent loss of pharmacologic
effect

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38
Q

f drug red is metabolized by CYP3A4 and
the drug yellow is also metabolized by CYP3A4. If
drug yellow induced the metabolism of drug red, will
there be an increase or decrease in the metabolism of the drug
red?

A

Increase in the metabolism of drug red.

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39
Q

What would happen to the effect of drug

red?

A

Decrease in effect. Since faster
metabolism of drug red. Drug yellow induces or
accelerates the metabolism of drug red.

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40
Q

Question: If you are given or prescribed with 2 drugs
and 1 drug induces the metabolism of the other drug.
How would you now address the situation to obtain
the desirable effect? Would you increase the dosage
of drug yellow or increase the dosage of drug red? Or
decrease dosage of drug yellow or decrease dosage
of drug red?

A

You can increase the dose of
drug red or decrease yellow or better is to change
drug yellow

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41
Q

Maximal effects usually occur after

A

7 to 14 days and
would require equal or longer time to dissipate after
the enzyme inducer is stopped

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42
Q

CYTOCHROME P450 (CYP) ENZYME INDUCTION

A

When a drug such as atorvastatin
(used to decrease your blood cholesterol;
mechanism: HMG-COA reductase inhibitor). So, your
atorvastatin here serves as the ligand, it enters the
cell and it can bind to nuclear receptor such as your
PXR, then PXR forms a complex with your RXR
(Retinoid X Receptor), and it binds to DNA upstream
of target genes. So, this binding would recruit your
coactivator which binds to your TATA box and
activates transcription by RNA polymerase.

43
Q

Aromatic HC

A

binds the ligand-binding domain of
soluble protein, AROMATIC HC RECEPTOR (AHR)
● Complex is transported to the nucleus by AHR
nuclear translocator (PROMOTES GENE
TRANSCRIPTION

44
Q

Aryl Hydrocarbon AHR

A

Omeparazole

45
Q

CAR (Androstane)

A

Phenobarbital

46
Q

PXR

A

Rifapmin

47
Q

FXR

A

Bile acid

48
Q

PPAR

A

Fibrates

49
Q

RAR

A

All trans retinoic acid

50
Q

RXR

A

9-cis Retinoic acid

51
Q

Induction

A

it would accelerate the
metabolism by inducing the synthesis of your
Cytochrome P450, reducing the effect of the ligand.

52
Q

The most common form of inhibition

A

through

competition for the same isozyme.

53
Q

drug red and then drug yellow,
wherein they are metabolized by the same CYP450,
but drug yellow is an inhibitor. So, what would be the
effect on the metabolism of your drug red

A

? It would

be enzyme inhibition.

54
Q

if there is decrease in the
metabolism of drug red, what would happen to its
biologic effect?

A

An increase in biological effect, It can increase the risk for toxicity.

55
Q

How would you address the problem in enzyme

inhibition wherein there is increased risk for toxicity?

A

Decrease the dose of drug red or you can change
drug yellow, as we are preventing drug-drug
interaction, to prevent toxicity

56
Q

most common is your CYP3A4

A

50% are metabolized by it

57
Q

CYP1A2, has

A

has substrate of
acetaminophen, with inducers of lansoprazole,
primidone, rifampin. Acetaminophen effect is not that
significant unless you give a toxic dose.

58
Q

carbamazepine and rifampin wherein

they are metabolized by your CYP2C8

A

if both drugs
are given where rifampin is an inducer, so meaning
rifampin would facilitate or accelerate the metabolism
of your carbamazepine, decreasing its effect but if
carbamazepine is given together with your
gemfibrozil (inhibitor), metabolized by the same CYP,
it would inhibit the metabolism of carbamazepine,
therefore the effect of carbamazepine is increased
when you give it concomitantly with gemfibrozil.

59
Q

● 16-year-old patient sought to consult due to a cough
of 2 weeks duration.
● He is known asthmatic. On PE, RR 45 with subcostal
retractions and wheezes and rales on both lungs.
With an impression of atypical pneumonia and
Bronchial asthma in acute exacerbation, Prednisone
and Salbutamol nebulization was given.
● Which of the following antimicrobials would be of
benefit for this patient?
a) Amoxicillin
b) Cefuroxime
c) Azithromycin
d) Clarithromycin

A

C Azithromycin

Drugs given were Prednisone and salbutamol,
Case is chlamydia

Azithromycin and Clarithromycin have
coverage for atypical microorganisms such as mycoplasma and chlamydia.

Prednisone is
metabolized by CYP3A4 then clarithromycin is an
inhibitor, considering drug-drug interaction,
prednisone concentration in the body would be
increased therefore increasing its effect and toxicity.
So, among these drugs, better to give azithromycin
as it has no drug interaction with prednisone nor
salbutamol.

60
Q

PHASE 2 REACTIONS

A

Parent drugs or their phase 1 metabolites that contain
suitable chemical groups often undergo coupling or
conjugation reactions with an endogenous substance
to yield drug conjugates.
• These reactions are synthetic, anabolic and involving
conjugations. Phase 2 reactions also occurred in the
liver. So, if your phase 1 is adding your functional
group which serves as a substrate where in the Phase
2 reactions, you conjugate the drug or you couple it to
yield drug conjugate.

61
Q

most reactions are via

A

UGT make table of phase 1 and phase 2 rxn tables.

62
Q

GLUCURONIDATION

A

Glucuronide formation involves the formation of a
high-energy phosphate compound, uridine
diphosphate glucuronic acid (UDPGA) → from which
glucuronic acid is transferred to an electron-rich atom
(N, O or S) on the substrate, forming an amide, ester
or thiol bond.

63
Q

UDP-glucuronyl

transferase.

A

This is an example of

glucuronidation reaction, via the addition of glucuronide

64
Q

SULFATION

A

Sulfotransferases (SULTs) are cytosolic and conjugate sulfate derived from 3ʹ-phosphoadenosine5ʹ-phosphosulfate (PAPS) to the hydroxyl and, less
frequently, amine groups of aromatic and aliphatic compounds.
• SULTs play an important role in normal human homeostasis.

65
Q

SULT2B1b

A

predominant form expressed in skin,

carrying out the catalysis of cholesterol.

66
Q

SULT2A1

A

highly expressed in the fetal adrenal

gland.

67
Q

SULT1A3 is

A

highly selective for catecholamines

68
Q

• SULT1E1

A

estrogen.

69
Q

GLUTATHIONE CONJUGATION

A

• The substrate in the reaction is a tripeptide
glutathione which is synthesized from glutamic acid,
cysteine, and glycine

70
Q

Glutathione exist in cell as oxidized or reduced form

and the ratio is critica

A

maintaining cellular

environment in reduced state.

71
Q

The glutathione-S-transferases (GSTs) catalyze the

transfer of glutathione to reactive electrophile

A

a function that serves to protect cellular
macromolecules from interacting with electrophiles
that contain electrophilic heteroatoms (-O, -N, and -S)
and in turn protects the cellular environment from
damage.

72
Q

ACETYLATION

A

There are two genes for N-acetylation, NAT1 and NAT2

73
Q

Example of a drug that undergoes N-acetylation

A

Isoniazid

74
Q

If the subject or the patient has a slow acetylator

gene,

A

decrease metabolism of isoniazid by Nacetylation, thereby increase in the risk for adverse
effect.

75
Q

hydralazine

A

which contains the
hydrazine group, undergoes N-acetylation, so if there
is genetic polymorphism, and the patient is a slow
acetylator type, and then you give hydralazine, which
is used in treating hypertension, it can aggravate
hypotension, tachycardia, and headache. But if the
patient is a rapid acetylator, there is decreased in the
effect of hydralazine as well as decreased side effect

76
Q

Acetaminophen, an analgesic antipyretic drug, is

quite safe in therapeutic doses (1.2 g/d for an adult).

A

It normally undergoes glucuronidation and sulfation to
the corresponding conjugates, which together make
up 95% of the total excreted metabolites. The
alternative P450-dependent GSH conjugation
pathway accounts for the remaining 5%. When
acetaminophen intake far exceeds therapeutic doses

77
Q

Acetaminophen metabolism via Phase 2, 95% would

undergo

A

glucuronidation as well as sulfation. Only 5%
is cytochrome P450 dependent GSH conjugate
pathway? At therapeutic dose, acetaminophen would
undergo this pathway and sulfation pathway

78
Q

there is toxic dose for acetaminophen

A

toxic dose is a single injection of 7.5-10g or acute
injection of 12g of acetaminophen, and for children
ingestion of more that 150mg/kg, so glucuronidation
reaction as well as sulfation reaction would be
saturated, so they cannot afford the excess
acetaminophen, there will be increase in the
metabolism via cytochrome P450 enzyme.

79
Q

treatment of acetaminophen toxicity

A

NAC, within 6-8 hours

80
Q

GENETIC FACTORS

A

A true genetic polymorphism is defined as the
occurrence of a variant allele of a gene at a population
frequency of ≥ 1%, resulting in altered expression or
functional activity of the gene product, or both

81
Q

PHASE 1 ENZYME POLYMORPHISM

A

It involves FOM, hydroxylases, as well as

cytochrome P450.

82
Q

Poor Metabolizer (PM)

A 
faulty expression of the P450 protein
due to either defective mRNA splicing or
protein folding, resulting in little or no
isoform-catalyzed drug metabolism.
o meaning, the Phase 1 reaction is
prolonged secondary to messenger
RNA defect
83
Q

Ultrarapid Metabolizer (UM)

A 
o most common in Ethiopians and Saudi
Arabians, populations that display it in
up to one-third of individuals
o require twofold to threefold higher daily
doses
o has fast drug metabolism
o for fast metabolizers or ultrarapid
metabolizers, to attain the therapeutic
the effect, increase the dose by two times or three times
84
Q

PHASE 2 ENZYME POLYMORPHISM

A 
. PHASE 2 ENZYME POLYMORPHISM
• The problem can be in conjugation,
acetylation, sulfation, methylation
• The commonly described is your acetylation
enzyme polymorphism Phase 2.
• So, they can be categorized as Slow
Acetylator or Rapid Acetylator
85
Q

SLOW ACETYLATOR PHENOTYPE

A

The defect in slow acetylators (of isoniazid and similar
amines) appears to be caused by the synthesis of
less of the NAT2 enzyme rather than of an abnormal
form of it.
• For Slow Acetylator Phenotype, mostly, their
polymorphism affects NAT2 than NAT1.
• 50% of blacks and whites in the USA, more frequently
in Europeans living in high northern latitudes
• Associated with a higher incidence of isoniazidinduced peripheral neuritis, drug-induced
autoimmune disorders, and bicyclic aromatic amineinduced bladder cancer

86
Q

Isoniazid is metabolized by a Phase II through Nacetylation. If the patient has the slow acetylator
phenotype, metabolism of your isoniazid is

A

Slow

87
Q

if there is
an increase in the effect of Isoniazid, it can increase
the adverse effects of Isoniazid such as

A

Peripheral Neuritis

88
Q

Hydralazine would also
undergo acetylation? If the patient has slow acetylator
phenotype, it can aggravate the hypotensive effect as
well as

A

tachycardia caused by your Hydralazine

89
Q

Sulfonamide, which also undergoes acetylation.

It can aggravate the side effect of your Sulfonamide

A

hypersensitivity reaction leading to druginduced autoimmune disorder.

90
Q

For Slow Acetylators,

A

f the drug is really needed,
you can decrease the dosage or prolong the
frequency of interval of administration of the drug
to reduce the risk for adverse effects.

91
Q

RAPID ACETYLATOR PHENOTYPE

A

Isoniazid, so decreased biologic effects of Isoniazid.
To achieve the therapeutic effects of Isoniazid to a
patient classified as Rapid Acetylator, you increase
the dosage.

92
Q

Charcoal-broiled foods ®

A

induce CYP1A enzymes

93
Q

Grapefruit juice ®

A

inhibit the CYP3A metabolism of

co-administered drug substrate

94
Q

Cigarette smoker ®

A

metabolize some drugs more
rapidly than nonsmokers because of enzyme
induction

95
Q

Industrial workers exposed to some pesticides ®

A

metabolize drug more rapidly

96
Q

Extremes of ages

A

increased susceptibility to

pharmacologic or toxic activity of drugs because of the decrease in metabolism

97
Q

eonates and children have limited

ability for xenobiotic biotransformation because:

A

At birth, the level of your cytochrome P450 is
diminished, and then as their age increases, the level
of cytochrome P450 also increases. However, the
effect and biologic activity of cytochrome P450 are
not that mature.

98
Q

Slower metabolism

A

Reduced activity of metabolic enzymes
o Reduced availability of essential endogenous
cofactors

99
Q

DRUG-DRUG INTERACTIONS DURING

METABOLISM

A

Overlapping substrate specificities by the CYPs is
one of the underlying reasons for the predominance
of drug-drug interactions.
• So, when 2 co-administered drugs are both
metabolized by your single cytochrome P450, they
compete to bind to the enzyme active site. So, this
drug can either induce or inhibit the metabolism of the
same drug. So, this refers to your drug-drug
interaction leading to the cause of your adverse
effect.

100
Q

An inducer may enhance not only the
metabolism of the other drug but also its own
metabolism

A

Atrovastatin

101
Q

Atorvastatin itself would induce the

synthesis of the cytochrome P450 enzyme

A

CYP3A4

102
Q

Cimetidine (H2 blocker). Which is
prescribed for Acid Peptic Disease. So, if Cimetidine
is given concomitantly with Warfarin (anti-coagulant).
Since Cimetidine is an enzyme inhibitor, there will be
decreased metabolism of Warfarin. S

A

So, there will be
an increase in effect of Warfarin, meaning, an
increased risk for bleeding.

103
Q

INTERACTIONS BETWEEN DRUGS &

ENDOGENOUS COMPOUNDS

A

steep dose-response curve or a narrow
margin of safety, potentiation of its therapeutic
and toxic effects may result

104
Q

. DISEASES AFFECTING DRUG METABOLISM

A

• Liver. Acute or chronic diseases that affect liver
architecture or function markedly affect hepatic
metabolism of some drugs. Isn’t it the primary organ
for biotransformation is your liver?
o Alcoholic hepatitis
o Active or inactive hepatitis
o Biliary cirrhosis
o Acute viral or drug-induced hepatitis
o Impair hepatic drug-metabolizing enzymes
(microsomal oxid

Pharmacology (19 decks)

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