Pharmacology - Drug Metabolism and Excretion (Exam 1) Flashcards
The general purpose of drug metabolism and excretion is to make the drugs more ______ soluble, so they will be excreted and not reabsorbed
water
Where does biotransformation occur?
many organs, but the LIVER is the most important
What are the 2 biotransformation reaction subdivisions?
- non-synthetic (oxidation, Phase I)
- synthetic (conjugation, Phase II)
What is a non-synthetic reaction?
addition of COOH, NH2, O, OH, SH
What is a synthetic reaction?
addition of group from endogenous cofactor (usually transferring something)
In a Phase I oxidation reaction, what is inserted into the drug or side product?
oxygen (usually OH group)
The insertion of oxygen into the drug or side product in Phase I oxidation reaction causes what to happen?
makes drug more hydrophilic (less lipophilic)
In a Phase I oxidation reaction, the reaction is catalyzed by which enzyme systems?
- cytochrome P450 system
- mono-oxygenase system
- mixed function oxidase system
What CYP families are responsible for most drug oxidation?
CYP1, CYP2, and CYP3
What are the components of the P450 system?
- smooth ER
- cytochrome P450
- NADPH cytochrome P450 reductase
- molecular oxygen
- NADPH
Put the following CYP families in order of importance:
CYP2D6, CYP2C, CYP3A
CYP3A (most important)
CYP2D6
CYP2C
Which CYPs are important for many clinical drugs?
CYP2C and CYP2D
Which CYP in the GI tract is important for the 1st pass effect?
CYP3A4
What are the 3 non-P450 oxidation reactions?
- alcohol and aldehyde oxidation
- purine oxidation
- monoamine oxidation
What are the other 4 metabolic reactions?
- azoreduction
- nitroreduction
- ester hydrolysis
- amide hydrolysis
What are the Phase II (conjugation/synthetic) reactions?
- glucuronidation (MOST COMMON)
- acetylation
- glutathione conjugation
- glycine conjugation
- sulfation
- methylation
What type of enzyme is used for the Phase II (conjugation/synthetic) reactions?
transferases
What are the factors affecting drug metabolism?
plasma protein binding, localization of drug in tissues, liver disease, and drug-drug interactions
Which drugs inhibit the cytochrome P450 system?
Cimetidine
Azole antifungals (ketoconazole)
Macrolide antibiotics (erythromycin)
During the induction of drug metabolism, there is an increase in ________ _________ proteins
cytochrome P450
During the induction of drug metabolism, _______ are classical and broad inducers that induce P450 to be produced
barbiturates
During the induction of drug metabolism, environmental ________ also induce more selectively
carcinogens
During the induction of drug metabolism, chronic ______ induces CYP2E1
alcohol
What are the 5 miscellaneous factors affecting drug metabolism?
- age
- diet
- disease
- other drugs
- environmental chemicals
During the formation of toxic metabolites, _______ intermediates form and bind to cellular macromolecules
electrophilic
The formation of toxic metabolites causes _________, ________, and __________.
necrosis, mutagenesis, and carcinogenesis
During the formation of toxic metabolites, ___________ conjugation is the first defense
glutathione
What are the principal excretion routes?
- renal (most important)
- biliary
- pulmonary
- miscellaneous (saliva, sweat, tears, milk)
What are the routes of renal excretion?
glomerular filtration, active tubular secretion, active tubular reabsorption, passive reabsorption
Where does glomerular filtration happen?
at the glomerular membranes
What is the capacity of glomerular filtration?
180 L/day
20% of plasma
(high capacity)
What are the requirements for drug filtration through the glomerulus?
-not too big
-not bound to plasma proteins
-lipid solubility/pH do NOT effect
How are anions and cations involved in active tubular secretion?
-organic anion transporters (OATs)
-organic anion transporter peptides (OATPs)
-organic cation transporters (OCTs)
(T/F) Active tubular secretion is saturable
true
(T/F) Active tubular secretion and biliary excretion are incompletely developed in a newborn
true
Is active tubular secretion specific or non-specific?
non-specific (causes competition)
During active tubular secretion, inhibition by drugs such as probenecid can depress renal excretion of other ______ _______ (ex: penicillin)
weak acids
What is the location and characteristics of active tubular reabsorption similar to?
active tubular secretion
During active tubular reabsorption, what is it important to conserve?
endogenous compounds (ex: uric acid)
What drugs inhibit active tubular reabsorption?
uricosuric drugs
What does passive reabsorption require?
non-ionized form of drug
(T/F) passive reabsorption involves energy
FALSE, there is no energy involved in passive reabsorption
During passive reabsorption, what is the extent of drug ionization dependent upon?
pKa and urinary pH
During passive reabsorption, urinary pH varies between _____ and _____, but can be manipulated with drugs to increase excretion of _______ or _______
5; 8; acids; bases
Biliary excretion usually follows what?
Phase II conjugation in the liver
What kind of transport processes are involved in biliary excretion?
multiple carrier-mediated transport
(T/F) Biliary excretion requires energy
true
(T/F) Biliary excretion is saturable
true
(T/F) Biliary excretion is specific
FALSE, biliary excretion is non-specific
What can occur during biliary excretion?
enterohepatic cycling
What impairs biliary excretion?
liver disease
What is pulmonary excretion important for?
gases and volatiles
(T/F) Pulmonary excretion is simplified diffusion into expired aire
true
During pulmonary excretion, the elimination rate is dependent upon what?
-respiration rate
-pulmonary blood flow
-solubility of the drug in blood
_______ soluble drugs are excreted more readily
poorly
(T/F) Alcohol is more soluble than nitrous oxide
true
alcohol is very soluble, so it is not excreted well through the pulmonary system; nitrous oxide is excreted very well through the pulmonary system
How can you increase phenobarbital excretion?
- phenobarbital is a weak acid
- ionized form is excreted; non-ionized form is reabsorbed
- alkaline urine increases fraction of ionized form
result = increased excretion; reduced reabsorption
How can you increase amphetamine excretion?
- amphetamine is a weak base
- ionized form is excreted; non-ionized form is reabsorbed
- acidic urine increases fraction of ionized form
result = increased excretion; reduced reabsorption
