Metabolism Flashcards
Define metabolism
Conversion of a drug to a more polar, water soluble, ionized substance usually with reduced pharmacological activity and toxicity
Give an example of when pharmacodynamics may not equal pharmacokinetics
When there is 0% blood level but still producing a pharmacological effect. (Drug is completely concentrated in organ)
List some sites of metabolism
- bloodstream
- kidneys
- brain (CNS active drugs)
- muscle tissue
- wall of GI tract (ex. bacteria)
- lungs
_____ = main organ of biotransformation
liver
What are the two types of hepatic metabolism?
Phase 1
Phase 2
List Phase 1 Metabolism processes
- oxidation (most common)
- hydrolysis
- reduction
List Phase 2 Metabolism processes
- glucuronidation (most common)
- sulfation
- acetylation
What type of metabolism do barbiturates undergo?
- glucuronidation
- oxidation
What type of metabolism do benzodiazepines undergo?
1st N-dealkylation (biologically active metabolite) 2nd hydroxylation (active) 3rd glucuronidation (inactive)
What type of metabolism does morphine undergo?
glucuronidation
morphine-6-glucuronide (active)
morphine-3-glucuronide (inactive)
What type of metabolism does codeine undergo?
10% demethylated to morphine
What type of metabolism do tranquilizing agents undergo (anti-psychotic agents)?
- oxidation (majority)
- glucuronidation (some)
What type of metabolism does cocaine undergo?
plasma esterases
What type of metabolism does ethanol undergo?
oxidation (zero order process)
Phase 1: Oxidation:
Most _____ phase 1 reaction
prevalent
Phase 1: Oxidation:
What does it require?
NADPH, molecular oxygen, heme-protein
Phase 1: Oxidation:
Important phase 1 oxidation reactions are performed by mixed function oxidases found in the ???
smooth endoplasmic reticulum
Phase 1: Oxidation:
Key element in the oxidative process is the hemeprotein cytochrome: ??
cytochrome P450 enzyme system
Describe the mechanism of P450 action
- Substrate (drug) enters the system
- NADPH acts as an electron donor
- chromophore absorbs at 450 nm
- O2 is entered into the system
- NADPH acts as an electron donor
- H+ is added, H2O is released to form the proposed “activated oxygen” species
- then you get the oxidized product
Substrate: R-H
Oxidized Product: R-OH
What is the format of isoenzymes of CYP?
CYPnXm
n = family X = subfamily
Drug metabolism carried out by which CYP families?
1, 2, and 3
Oxidative phase 1 reactions are carried out by CYP in the presence of _____ and ______ _____
NADPH
molecular oxygen
The metabolism of drugs in humans is dominated by ___ major P-450 isoenzymes
six
What are the six major P-450 isoenzymes?
CYP1A2 CYP2C8/9/10 CYP2C18/19 CYP2D6 CYP2E1 CYP3A4
CYP1A2:
Substrates?
phenacetin, theophylline
CYP2C8/9/10:
Substrates?
hexobarbital, phenytoin
CYP2C18/19:
Substrates?
diazepam, mephenytoin
CYP2D6:
Substrates?
imipramine, propranol
CYP2E1:
Substrates?
acetaminophen
CYP3A4:
Substrates?
erythromycin, cyclosporin
CYP1A2:
Metabolizes ____ and ______
chemicals
toxins
CYP1A2:
____ induces this enzyme, resulting in activation of benzpyrene
smoking
benzpyrene - carcinogen in the cigarette smoke
CYP2C9, CYP2C19:
exhibits genetic ________
polymorphism (5% of caucasians, 20% of asians are poor metabolizers)
CYP2C9, CYP2C19:
Inhibition of S-warfarin metabolism by _______
amiodarone (high prothrombin times for 3 weeks)
CYP2D6:
More than ___ clinical drugs metabolized by this isoform
80
CYP2D6:
Also exhibits _____
polymorphism (ultra rapid metabolizers needing high doses)
CYP3A4:
More than _____ clinical drugs metabolized by this isoform
150
calcium channel blockers, bnezo’s, cyclosporin, etc
CYP3A4:
70% of iso form present in ___
gut (which decreases bioavailability)
What major drug-metabolizing isozymes does nutrition affect?
1A2, 2E1, 3A3
What major drug-metabolizing isozymes does smoking affect?
1A2
What major drug-metabolizing isozymes does alcohol affect?
2E1
What major drug-metabolizing isozymes does drugs affect?
1A2, 2C, 2D6, 3A3
What major drug-metabolizing isozymes does somatic (liver function and size, intestinal metabolism, etc.) affect?
1A2, 2E1, 3A3
What major drug-metabolizing isozymes does genetic polymorphism affect?
2C9, 2C19, 2D6, 2E1
Smoking induces 1A2, therefore ____ levels of drugs may be required by smokers than non-smokers (ex. theophylline)
higher
Chronic alcoholism induces ______ and glutathione depletion leading to accumulation of ____, a lethal byproduct of acetaminophen which leads to severe liver injury and possibly liver failure.
CYP2E1
NAPQ1
What are the two major reduction reactions?
Nitro-reduction
Azo-reduction
What carries out the reduction reactions?
Intestinal microflora carries out these reactions with far more efficiency than livers in mammals.
______ = performed through respective esterases in the liver. Also by esterases in plasma and other tissues. Esterases hydrolyse esters to alcohols and carboxylic acids. Ex. procaine
Hydrolysis
Hydrolysis can also be simply defined as ??
addition of a water molecule
Oxidation is _____
losing
Reduction is _____
gaining
What do phase 2 reactions generally increase?
the water-solubility of a molecule
-which then results in pharmacological deactivation
For phase 2 reactions to occur, a compound must be chemically ______.
active
Phase 1 reactions make the compound chemically _____
active
Is it possible to skip phase 1 metabolism and just go straight to phase 2?
Yes - if the compound is already chemically active
ex. sulfanilamide
ex. procainamide
List some factors affecting drug metabolism
- species
- genetics
- age
- disease state
- drug/drug interactions
- food
Where does glucuronidation happen?
endoplasmic reticulum
Where does salvation occur?
cytosol
Where does acetylation occur?
cytosol
Where does methylation occur?
cytosol and ER (endoplasmic reticulum)
Where does glutathione conjugation occur?
cytosol and ER
Endogenous substrates involved in glucuronidation?
steroids
thyroxine
catecholamines
bilirubin
Endogenous substrates involved in sulfation?
steroids
carbohydrates
Endogenous substrates involved in acetylation?
serotonin
Endogenous substrates involved in methylation?
biogenic amines
Endogenous substrates involved in glutathione conjugation?
metabolites of arachidonic acid
What does NAT-2 stand for?
N-acetyltransferase 2
Since isoniazid is _____ and N-acetylisoniazid is not, the rate and extent of metabolism will affect the efficacy of the drug in treating tuberculosis (fast and slow acetylators)
active
Total body water and extracellular fluid in newborn __ adult
>
What happens when you become elderly?
- lean body mass decreases
- body fat increases
- *in relation to body weight
What happens if you’re a newborn?
- low titers of hepatic microsomal enzymes
- glucuronidation reactions decrease
Is the Vd of a drug higher or lower in newborns compared to children?
higher in newborns man
____-____ is a lot longer for newborns compared to adults
half-life
How does a decreased protein diet affect drug metabolizing capacity?
it decreases it
How does decreased lipid intake and decreased EFA (essential fatty acids) affect metabolism of ethylmorphine & hexobarbitone?
decreases the metabolism
How does high glucose intake affect barbiturate metabolism?
inhibits the barbiturate metabolism
How does food increase bioavailability?
By increasing splanchnic blood flow
What are charcoal broiled meats & smoked fish potent inducers of?
cytochrome P450 enzyme systems
How does grapefruit juice affect P450 enzymes?
Grapefruit juice inhibits intestinal P450 enzymes which increases bioavailability of cyclosporine
Grapefruit juice is a potent inhibitor of _____
CYP3A
What is CYP3A responsible for?
the metabolism (hence excretion) of antihistamines, benzodiazepines, immunosuppressants, etc.
Are juices safe with drugs?
NO - take with water
Are herbs safe with drugs?
no way jose
How long do the effects of flavonoids and furanocoumarins (found in grapefruit juice) last for?
at least 3 days following ingestion
How does St. John’s wort affect CYP3A?
induces it
*produces sub therapeutic doses of HIV treating drugs
What is St. John’s wort used for?
treating mild to moderate depression
What is ginseng used for?
used as a normalizer, energizer, and stress reducer
What does ginseng have potential interactions with?
- anti-depressants (headache & mania)
- warfarin (increased bleeding time)
- steroids (stronger effects)
How does Ginko, garlic interact with warfarin?
increases bleeding time with warfarin (risk of hemorrhages)
What is the Michaelis-Menton Equation?
Rate of metabolism = VmaxC/(Km+C)
Rate of metabolism = VmaxC/(Km+C)
What does C = ?
[drug]
Rate of metabolism = VmaxC/(Km+C)
What does Vmax = ?
maximum rate
Rate of metabolism = VmaxC/(Km+C)
What does Km = ?
Michaelis constant = 0.5 Vmax
Most drugs follow a ____ order process
first
*this produces a linear graph
Why is dealing with non-linear drugs a problem?
They produce a curved graph.
So when you want to double a dose, you will not be doubling the effect (it will have much more than double the effect)
*see slide 32
