(P) METABOLIC CHANGES OF DRUGS

Question 1

• Functionalization reactions
• Includes Oxidative, reductive and hydrolytic biotransformations
• Purpose is to introduce a functional polar group(s) (Ex: OH, COOH, NH2, SH) into the xenobiotic molecule to produce a more-water soluble compound

Answer 1

Phase 1

Question 2

• Mixed Function Oxidase System

Answer 2

Oxidation

Question 3

• Responsible for transferring an oxygen atom to the substrate
• Contains Iron and Copper

Answer 3

Cytochrome P450 (Wavelength)

Question 4

Examples of CYP450

Answer 4

• CYP3A4
• CYP2D6

Question 5

most dominant isoform of Cytochrome P450 in the liver

Answer 5

CYP3A4

Question 6

Antidepressants

Answer 6

CYP2D6

Question 7

Cytochrome P450 Enzymes Nomenclature

Answer 7

• CYP
• Arabic Number
• Capital Letter

Question 8

Cytochrome P450 enzymes

Answer 8

CYP

Question 9

• Family (CYP1, CYP2)
• Must have more than 40% identical amino acid sequence
• Individual enzyme in a subfamily (CYP1A2, CYP2C9)

Answer 9

Arabic Number

Question 10

• Subfamily (CYP1A, CYP2C, CYP3A)
• Must have more than 55% identical amino acid sequence.

Answer 10

Capital Letter

Question 11

The CYP enzymes are ____

Answer 11

Heme proteins

Question 12

The heme portion is an iron-containing porphyrin
called ______

Answer 12

Protoporphyrin IX

Question 13

And the protein portion is called ______

Answer 13

Apoprotein

Question 14

• Oxidation of Alcohols

Answer 14

Primary: Aldehyde > Carboxylic Acid
Secondary: Ketone
Tertiary: do not oxidize under normal conditions

Question 15

• plays an important role in the metabolism of many compounds containing carbonyl, nitro and azo group
• carbonyl compounds are converted to alcohol derivatives while nitro and azo are converted to amino derivatives
• Reduction of Aldehydes and Ketones to Alcohol
(Chloral Hydrate (date rape/knock-out drops)&raquo_space; Trichloroethanol

Answer 15

Reduction

Question 16

• for drugs containing the ester/amide functionality
• water is used to breakdown chemical bonds (addition of water)

Answer 16

Hydrolysis

Question 17

• Conjugation Reactions
• involve attaching small, polar, and ionizable molecules (like glucuronic acid, sulfate, or glycine) to Phase I metabolites or drugs. This makes them water-soluble, allowing easier excretion from the body through urine or bile.

Answer 17

Phase 2

Question 18

are readily excreted in the urine and are generally devoid of pharmacological activity and toxicity in humans.

Answer 18

Conjugated metabolites

Question 19

terminate or attenuate biological activity

Answer 19

Methylation and Acetylation

Question 20

protects the body against chemically reactive compounds and metabolites.

Answer 20

Glutathione (GSH) Conjugation

Question 21

• Most common
• Morphine, Paracetamol, Chloramphenicol (Gray Baby Syndrome)
• Glucuronyl transferase

Answer 21

Glucuronidation

Question 22

• Well-developed in infants
• Ex: Paracetamol

Answer 22

Sulfate Conjugation

Question 23

• used to conjugate carboxylic acids
• Ex: Benzoic acid to hippuric acid

Answer 23

Glycine & Glutamine Conjugation

Question 24

• an important pathway by which chemically reactive electrophilic compounds are detoxified
• free radical scavenger

Answer 24

Glutathione or Mercapturic Acid Conjugation

Question 25

• a tripeptide (glutamyl-cysteinylglycine)

Answer 25

Glutathione or GSH

Question 26

• acetyl group utilized is supplied by acetyl CoA • important for drugs containing primary amino groups • Hydralazine (SLE), Isoniazid (Peripheral Neuropathy), Sulfonamides (crystalluria) • uses N-acetyltransferase enzyme • primary function is to terminate pharmacological activity and detoxification

Answer 26

Acetylation

Question 27

• Systemic Lupus Erythematosus • autoimmune disease; more common in female • antigen and antibody complex

Answer 27

SLE

Question 28

SLE-like symptom

Answer 28

Malar Rash or Butterfly Rash

Question 29

PIMPCH stands for?

Answer 29

• Procainamide • Isoniazid, • Methyldopa • Chlorpromazine • Hydralazine

Question 30

• inactivation of physiologically active biogenic amines • does not lead to polar or water-soluble metabolites but are pharmacologically inactive

Answer 30

Methylation

Question 31

Sites of Drug Biotransformation

Answer 31

• Liver • Intestinal Mucosa • First-pass effect

Question 32

the most important organ in drug metabolism and detoxification of endogenous and exogenous compounds.

Answer 32

Liver

Question 33

• important site especially for orally administered drug • contains CYP3A4 isozyme and P-glycoprotein that can capture drug and secrete it back into the intestinal tract.

Answer 33

Intestinal Mucosa

Question 34

• orally administered drugs pass through the liver and are susceptible to hepatic metabolism before reaching the bloodstream • can decrease oral bioavailability

Answer 34

First-Pass Effect

Question 35

Drugs Metabolized Extensively by First-Pass Effect

Answer 35

• Isoproterenol • Pentazocine • Lidocaine • Propoxyphene • Meperidine • Propanolol • Morphine • Salicylamide • Nitroglycerin

Question 36

Enzyme Induction(PPRCC)

Answer 36

• Phenytoin • Phenobarbital • Rifampicin • Chronic Alcoholism • Carbamazepine

Question 37

Enzyme Inhibitors (MEDICKAV)

Answer 37

• Metronidazole • Erythromycin • Disulfiram • Isoniazid • Cimetidine • Ketoconazole • Acute Alcoholism • Valproic Acid