Pharm Topic 3: Drug Biotransformation And Excretion

Front 1

What is the key organelle for drug metabolism?

Back 1

Smooth ER

Front 2

Goal of the Phase 1 Rx and some examples

Back 2

Usually convert the parent drug into a reactive polar metabolite:
-p450 oxidation
-Oxidation
-Reduction
-Hydrolysis
-Hydroxylation

Front 3

Goal of phase 2 Rx and examples

Back 3

Conjugate drug with highly polar compounds which are very water soluble and easily excreted in urine:
-glucouronidation

Front 4

Microsomes

Back 4

Artificially generated organelles consisting of smooth and rough ER vesicles after homogenization of the liver.

Front 5

2 major components of the monooxygenase system

Back 5

Cytochromoe p450 and NADPH-cytochrome p450 reductase.

Front 6

Cytochrome p450

Back 6

Name for a superfamily of enzymes that catalyze the oxidative metabolism of many endogenous substances, drugs, and environmental chemicals.

Front 7

Cytochrome enzymes responsible for drug metabolism

Back 7

CYP 1-4 (mostly 1-3 though)

Front 8

Microsomal Flavin-Containing Monooxygenase (FMO)

Back 8

AKA Amine oxidase. Is a p450 independent oxidizing system.
Catalyzes oxidation of phenlethylamine and epi.

Front 9

Alcohol Dehydrogenase (ADH)

Back 9

Is a p450 independent oxidation system which catalyzes metabolism of alcohol. While CYP2E1 also metabolizes alcohol, it is only present in the liver where ADH is present in more places than just the liver and also processes other endogenous alcohols.
Are inhibited by Pyrazole compounds.

Front 10

Xanthine Oxidase

Back 10

p450 Independent oxidation system which is involved in uric acid synthesis.
Produces free radicals and may be part of reperfusion injury.
Inhibited by Allopurinol.

Front 11

What are the 6 key conjugation Rxs

Back 11

1) Glucuronidation
2) sulfate conjugation
3) Glutathione conjugation
4) Glycine conjugation
5) Acetylation
6) Methylation

Front 12

Induction of drug transformation

Back 12

Exposure to one drug enhances the metabolism of itself or another drug.

Front 13

6 Consequences of Enzyme Induction

Back 13

1) Increases rare of hepatic biotransformation of the drug
2) Increases rate of production of metabolites
3) Increases hepatic drug clearance
4) Decreases serum half life
5) Decreases serum and total and free drug concentrations
6) Decreases pharmacological effects if metabolites are inactive.

Front 14

Reversible Inhibition and example

Back 14

Due to competition for a binding site. After inhibitory agent is removed, normal function of isozyme returns.
Ex. Cinmetidine

Front 15

Metabolite Intermediate complexation and example

Back 15

p450 converts a non-inhibatory drug into a an effective inhibator b/c it binds the isozyme in a catalytically nonfunctional state.
Ex. macrolide antibiotics (erythromycin)

Front 16

Autocatalytic Inactivation and example

Back 16

Conversion of drugs into highly reactive free radicals which alkylate the enzyme and and inactivate it. De novo synth of new isozyme must occur to get restoration of drug metabolizing capacity.
Ex. chlorampenicol

Front 17

Cimetidine

Back 17

Antagonist of histamine at H2 receptor. Is used to treat peptic ulcers and other diseases where acid reduction is necessary.
Inhibits cytochrome p450 via reversible inhibition for Warfarin, Benzodiazepines, Phenytoin, and Morphine.

Front 18

Disulfiram

Back 18

While has no pharmacologic effect on its own, causes bad symptoms if mixed with alcohol. Inhibits aldehyde dehydrogenase. Used to treat alcoholism.

Front 19

6 Consequences of Inhibition of microsomal enzymes

Back 19

1) Decreases rate of hepatic biotransformation
2) Decreases rate of production of metabolites
3) Decreases total clearance
4) Increases serum halflife
5) Increases serum and total free drug concentrations
6) Increases phramacological effects if metabolites are inactive.

Front 20

First pass metabolism

Back 20

Following oral administration, a drug is taken to the liver via portal circulation where it may be metabolized very well. This can greatly reduce the bioavailability of a drug taken orally.

Front 21

Effect of age on biotransformation

Back 21

1) Low activity of a particular enzyme in neonates can lead to gray baby syndrome.
2) Decreased hepatic enzyme activity in the elderly.

Front 22

Effect of pathology on biotransformation

Back 22

1) Decreased hepatic enzyme activity in hepatitis can lead to increase drug half life.
2) Low levels of hepatic and non hepatic enzymes in uremic patients leads to increased drug response.

Front 23

Effects of genetics on biotransformation

Back 23

Polymorphisms of liver enzymes can lead to variation. Example is people are either fast or slow acetylators.

Front 24

Effects of induction on biotransformation

Back 24

Leads to a decrease in plasma concentration, half life, and pharmacological response.

Front 25

3 ways the kidneys deal with drugs or metabolites

Back 25

1) Glomerular filtration - Large amount of drugs go from blood to tubules. Excludes molecules based on size but not charge.
2) Active secretion into tubule - Via enzymes. Secretes acids and bases, and can pass molecules against a [] gradient so that plasma [] gets to near zero.
3) Passive reabsorption - Lipid soluble unionized drugs can be reabsorbed in this fashion. This is why drugs with high lipid solubility are slowly excreted.

Front 26

Effect of intestinal bacteria on some drugs metabolism

Back 26

Can cause conjugated drugs due for excretion via thew bile to become unconjugated by bacterialglucouronidase and get reabsorbed into the blood.

Front 27

Which p450 enzyme breaks down alcohol

Back 27

CYP2E1

Front 28

10 Drugs which undergo significant first pass metabolism

Back 28

1) Aspirin
2) Gyceryl trinitrate
3) Isosorbide dinitrate
4) Levodopa
5) Lidocaine
6) Metoprolol
7) Morphine
8) Propranolol
9) Salbutamil
10) Verapamil

Front 29

Prodrug

Back 29

Substance where parent compound lacks activity on its own but becomes active after metabolism.

Front 30

Synthetic Reactions (metabolites, Rxs catalyzed by microsomal and non-micro enzymes, rate dependence)

Back 30

Metabolite is less lipid soluable and pharmacologically inactive.
Microsomal - Glucuronide conjugation. Rate can be effected by drugs
Non - All except glucuronide. Rate cannot be effected by drugs.

Front 31

Nonsynthetic Reactions (metabolites, Rxs catalyzed by microsomal and non-micro enzymes, rate dependence)

Back 31

Metabolites - Less lipid soluable but may be more or less active.
Microsomal - Most oxidations, reductions, and some hydrolyses. Rate can be effected by agents.
Non - Most hydrolyses, some oxs and reductions, no stim of rate by other drugs