What secondary enzyme also metabolizes warfarin (other than CYP)?
VKORC1 (vitamin K epoxide reductase complex protein 1)
What 3 drugs are great examples of genes affecting response to drugs (pharmacogenomics)?
warfarin
atomoxetine (strattera for ADHD)
irinotecan (anticancer)
Which enzyme metabolizes atomoxetine (strattera)?
2D6
Which drug has 15 different alleles in the encoding gene for metabolism?
atomoxetine (strattera)
What is the the indication of Irinotecan?
anticancer
What is the indication of atomoxetine?
ADHD
What is the MOA of Irinotecan?
topoisomerase inhibitor
What enzyme metabolizes irinotecan?
UDP-glucuronosyltransferase 1A1
Which drug has a decreased activity in 10% of cancer patients leading to a 5-fold increase in side effects because they do not have the enzyme?
irinotecan
don't have UDP-glucuronyltransferase 1A1
What anticoag drugs are inhibited by CYP2B6?
Ticlopidine
Clopidogrel
Thiolactone metabolite of Prasugrel
What are some drugs that enhance metabolism (enzyme induction)?
phenobarb
other barbiturates
glutethimide
phenylbutazone
meprobamate
ethanol
phenytoin
rifampin
griseofulvin
carbamazepine
What is the indication of Glutethimide?
piperidine based sedative hypnotic
What sedative hypnotic undergoes selective hydroxylation to create 2 different enantiomers in a mixture?
glutethimide
Which anti-seizure drug is metabolized into 10% 'R' enantiomer and 90% 'S' enantiomer?
Phenytoin
Which smooth muscle relaxant/peripheral vasodilator undergoes regioselective metabolism by demethylation?
Papaverine (Pavabid)?
Papaverine
Pavabid
What is the indication of Papaverine (Pavabid)?
smooth muscle relaxant used as a peripheral vasodilator
Which two drugs can create metabolites that are active and toxic?
Nevirapine (AIDS)
Procainamide (anti-arrythmic)
What specific metabolite created from Paroxetine can inactivate CYP2D6?
carbene
What drug does the metabolite carbene come from?
paxil (paroxetine)
How many CYP enzymes does the human genome code for?
at least 57
What enzyme metabolizes more than 50% of drugs?
CYP3A4
Which local anesthetic is de-ethylated (oxidative dealkylation) during the first-pass effect into acetylaldehyde? Also classified as a tertiary aliphatic/alicyclic amine oxidation...
Lidocaine
What is the indication of Lidocaine?
local anesthetic
ventricular arrythmias during acute MI or cardiac sx
post-herpatic neuralgia caused by herpes zoster infection
What drug cannot be given oral for ventricular arrythmias and why?
Lidocaine
b/c first pass effect deactivates the metabolites
What drug has metabolites that can cause neurotoxicity/seizure and must be closely monitored during an IV?
lidocaine
Which drug undergoes a series of metabolic steps prior to urine excretion, can be found in the urine 60-90 days after use, and 6 months after use in hair?
9THC (marijuana, tetrahydrocannabinol)
Which ant-seizure (anti-epileptic) drug undergoes oxidation via an intermediate arene oxide (epoxide) and a hydride shift?
Phenytoin (Dilantin)
Which three drugs undergo selective oxidation?
Diazepam
17-alpha-ethinylestradiol
Bromobenzene
Diazepam
Valium
17-alpha-ethinylestradiol
oral contraceptive
What is the indication of Diazepam(Valium)?
anti-seizure
muscle relaxant
___ is a terrible liver toxin because the epoxide it creates reacts with DNA and RNA? Was used during WWII. Attaches to either water or GSH
bromobenzene
Metabolism of this can lead to a carcinogen b/c of the epoxide it creates in the liver?
What is an example of a drug that creates an epoxide that can be isolated from the urine and has even been found in drinking water in CA? In this case, the epoxide metabolite is the ACTIVE drug. Oxidation of C=C olefin.
Carbamazepine (Tegretol)
Carbamazepine
Tegretol
What is the indication of carbamazepine (tegretol)?
partial and clonic-tonic seizures (anticonvulsant)
What is another drug that undergoes olefinic oxidation via an intermediate epoxide?
Secobarbitol
Secobarbitol
Seconal
What is the indication of secobarbitol?
short duration anesthetic
What are two drugs that undergo benzylic oxidations?
Metoprolol
Tolmetin
Metoprolol
lopressor
Tolmetin
Tolectin
What is the indication of metoprolol?
beta blocker
What is the indication of tolmetin?
anti-inflammatory analgesic
What are three drugs that undergo allylic oxidation?
Pentazocine (Talwin)
Quinidine
Hexobarbitol
Pentazocine
Talwin
What is the indication of Pentazocine (Talwin)
narcotic used for pain
used for pre- or post op anesthesia
Quinidine
Quinidex Extendtabs
Quinaglute Dura Tabs
Quinalan
Cardioquin
What is the indication of quinidine?
anti-arrythmic
Which quinidine brand causes GI upset?
Quinidex Extendtabs (sulfate salt)
Which form of quinidine cause much less GI upset?
the sugar salts (compared to the sulfate salt)
What is the indication of glutethimide?
insomnia (use for 3-7 days)
What are two drugs that are oxidated at an alpha carbon next to carbonyl or an imine?
Diazepam
Glutethimide
What is Diastat?
rectal diazepam gel
anticonvulsant
Why would you use Diastat?
if you have N/V and you can't keep your oral anticonvulsant down
also for anxiety, skeletal muscle relaxant
What drug does the metabolite Oxazepam stem from?
diazepam
Oxazepam
Serax
What is Oxazepam used for?
anxiety
for detoxing an alcoholic
What are two drugs that undergo aliphatic oxidation?
Ibuprofen
Chlorpropamide (Diabinese)
What is the indication for Chlorpropamide?
oral anti-diabetic sulfonylurea
Chlorpropamide
Diabinese
What are two drugs that undergo oxidation at alicyclic carbons?
Acetohexamide (dymelor)
Minoxidil (Loniten, Rogaine)
What is the indication of Acetohexamide (Dymelor)?
oral antidiabetic sulfonylurea
What is minoxidil indicated for (two things)?
severe unresponsive hypertension (loniten)
male pattern baldness (rogaine)
What are 4 examples of tertiary aliphatic and alicyclic amine oxidations?
Chlorpromazine (Thorazine)
Nicotine
Lidocaine
Tamoxifen Citrate (Nolvadex)
What is the indication of Chlorpromazine (Thorazine) and Phenothiazine?
antiemetic
antivertigo
antipsychotic
tab, cap, supp, syrup, injection
What drug cause the thorazine shuffle?
chlorpromazine (thorazine) or phenothiazine
it is neurotoxic
What is the the #1 drug for treating breast cancer?
tamoxifen citrate (nolvadex)
What are 4 examples of oxidations of primary and secondary amines?
Propanolol (Inderal)
Methylphenidate (Ritalin)
Phentermine (Ionamin, Adipex-P, Zantryl, Fastin)
(dl)-Amphetamine sulfate
What is propranolol indicated for?
beta blocker (non-selective)
test anxiety/stage fright
Propanolol
Inderal
Methylphenidate
Ritalin
What is the indication of Methylphenidate?
ADHD
narcolepsy
Phentermine HCl
Fastin
Zantryl
Adipex-P
Ionamin
What is phentermine indicated for?
appetite suppressant
managing obesity
used to study hardcore
What is (dl)-Amphetamine sulfate indicated for?
ADHD
narcolepsy
What drug makes metabolites like an imine, an oxime and phenylacetone, which can be found in the urine of meth users?
(dl)-Amphetamine sulfate
What are two drugs that undergo oxidation of nitrogen heterocycles?
in combo to make Septra, used for UTIs and pcp (HIV pneumonia)
What 2 drugs undergo oxidation of an amide?
Diazepam ---> DesmethylDiazepam
Cyclophosphamide (Cytoxan, Neosar)
What is the indication of cyclophosphamide?
alkylating agent (anticancer)
Which drug has to be a prodrug in order to be active and the metabolite it creates can cause hemorrhagic cystitis? What is the name of the metabolite?
Cyclophosphamide= drug
Phosphoramide Mustard= active prodrug
Metabolite= Acrolein
Which drugs undergo oxidation of a carbon-oxygen system (O-dealkylation)?
codeine----> morphine
trimethoprim
metoprolol
prazosin
indomethacin
T/F: codeine is active in itself.
false
What prodrug arises from codeine and is actually the active form of the drug, which some people do not ever get to experience if they are slow metabolizers?
morphine comes from codeine
Which drug undergoes desulfurization?
Thiopental (Pentathol)
What is Thiopental indicated for?
induces anesthesia to get you through stage 1 of anesthesia so you don't vomit
Thiopental
Pentathol
Which drug undergoes sulfur oxidation?
Thioridazine (Mellaril)
Thioridazine
Mellaril
What is thioridazine indicated for?
antipsychotic tranquilizer
What is a metabolite of Thioridazine (mellaril) that is not as toxic and is a good antipsychotic?
Mesoridazine (Serentil)
What is a drug that undergoes oxidative dehalogenation?
Halothane (Fluothane)
What is halothane indicated for?
general anesthesia
Halothane
Fluothane
What is the huge problem with Halothane, which is metabolized by oxidative dehalogenation?
it causes severe liver damage because it creates a fluorocarbon and HCl (10,000 times more acidic than vinegar)
Name a drug that undergoes oxidative aromatization.
Norgestrel (Progestin)
Name a drug that undergoes stereospecific ketone reduction.
R (+) Warfarin
What are two drugs that undergo reduction of a nitro or azo compounds?
Dantrolene (Dantrium)
Sulfasalazine (Azulfidine)
What is Dantrolene indicated for?
direct acting skeletal muscle relaxant used in spasticity, malignant hyperthermia with seizures
What is sulfasalazine indicated for?
sulfonamide antibiotic and antiinflammatory used to treat ulcerative colitis and rheumatoid arthritis
Sulfasalazine
Azulfidine
Dantrolene
Dantrium
What are two drug that undergo miscellaneous reductions?
Disulfiram (Antabuse)
Sulindac (Clinoril)
What is disulfiram indicated for?
chronic alcoholism
What is sulindac indicated for?
NSAID
Which drug undergoes a reduction in the liver (which is rare) and begins with a sulfoxide prodrug?
sulindac (Clinoril)
Which drug undergoes ester hydrolysis?
aspirin (ASA)
What are two other examples of hydrolysis of esters or amides? (reduction section)
Clofibrate (Atromid-S)
Prazosin (Minipress)
What is the indication of Clofibrate?
antihyperlipidemic
Clofibrate
Atromid-S
Prazosin
Minipress
What is the indication of Prazosin?
antihypertensive
alpha 1 blocker
Which are harder to hydrolyze in the body, amides or esters?
amides
Many prodrugs are _____? Hint: easily hydrolyzed in the body
esters
What is an -enol drug that undergoes oxygen glucuronidase conjugation (phase II)?
warfarin sodium
Which alcohol hydroxyl drug undergoes glucuronidation?
Chloramphenicol (Chloromycetin)
What is the indication of Chloramphenicol?
serious infections, monitor for blood dyscrasias
What is a phenol hydroxyl drug that undergoes glucuronidation?
APAP
What is a carboxylate hydroxyl example of glucuronidation?
Fenoprofen (Nalfon)
Chloramphenicol
Chlormycetin
Fenoprofen
Nalfon
What is the indication of Fenoprofen?
NSAID
What is an example of N-hydroxyl glucuronidation?
Dapsone
What is Dapsone indicated for?
txt of brown recluse spider bites
leprosy
pcp (pneumocystitis carinni pneumonia)
What are two drugs that undergo sulfate conjugations (phase II)?
Alpha-Methyldopa (Aldomet)
Albuterol (Proventil, Ventolin, Airet)
Alpha-methyldopa
Aldomet
Albuterol
proventil
airet
ventolin
What is aldomet indicated for?
antihypertensive
What is albuterol indicated for?
bronchospasms in COPD
What is a drug that is conjugated with glycine?
Isoniazid (Laniazid, Nydrazid)
Isoniazid
Laniazid
Nydrazid
What is Isoniazid indicated for?
TB
What are two drugs that undergo Glutathione (GSH) nucleophilic displacement conjugation?
Nitroglycerin
Azathioprine (Imuran)
What is Nitroglycerin indicated for?
nitrate vasodilator for treatment and prophylaxis of angina
Azathioprine
Imuran
What is azathioprine indicated for?
immunosuppressant used to txt transplantation and rheumatoid arthritis
What drug leads to the active immunosuppressant mercaptopurine?
Azathioprine
What are two drugs that undergo GSH Michael Addition phase II conjugation?
APAP
Ethacrynic Acid (Edecrin)
What is Ethacrynic acid indicated for?
loop diuretic used to rid edema in CHF, renal and liver diseases= lots of urine produced to rid edema
ethacrynic acid
Edecrin
What toxic metabolite does APAP generate when undergoing phase II Michael addition GSH conjugation?
iminoquinone = liver failure
*reason why you should not drink alcohol and take APAP with or for hangover
What are two drugs that undergo N-acetylation?
Clonazepam (Clonipin)
Hydralazine (Apresoline)
What is clonazepam indicated for?
anticonvulsant benzodiazepine
Clonazepam
Clonipin
Hydralazine
Apresoline
What is hydralazine indicated for?
antihypertensive vasodilator
Which antihypertensive vasodilator has ~20 metabolites?
hydralazine (apresoline)
Which drug shows treatment failure because of fast acetylators?
isoniazid
Which drug can have covalent binding in liver cell macromolecules leading to liver damage?
isoniazid
Norepinephrine, dopamine, serotonin, and histamine are all biogenic amines that are inactivated by what 2 methylation molecules?
SAM
methyltransferase enzymes
Which enzyme is responsible for inactivating dopamine and norepinephrine?
COMT
What are two drugs that undergo methylation via COMT?
Levodopa (Larodopa, Dopar)
Terbutaline (Berthaire, Brethine, Bricanyl): not really though b/c of 1,3 position
What is a resorcinol that is NOT a substrate for COMT because of the 1,3 position of hydroxyls?
Terbutaline
What is Terbutaline indicated for?
sympathomimetic bronchodilator
What position do the hydroxyls have to be to be substrates for COMT?
1,2
What drug do you have to co-administer with Levodopa?
carbidopa
Levodopa
Larodopa
Dopar
Terbutaline
Brethine
Bricanyl
Berthaire
What are 2 drugs that undergo methylation via N-methyl transferase?
amantadine (symmetrel)
nicotine
Amantadine HCl
Symmetrel
What is amantadine indicated for?
Parkinson's
type A flu virus
What is a drug that undergoes methylation via S-methyl transferase?
Propylthiouracil
What is propylthiouracil indicated for?
hyperthyroidism by preventing synthesis of T3 and T4
Why is grapefruit juice bad?
the flavenoids in it inhibit p-glycoproteins in the GI tract = no absorption of drug
Name 5 drugs that have been taken off the market due to DIs causing torsades depointes/QT elongation?
Terfenadine (Seldane): antihistamine
Mibefradil (Posicor)
Astemizole (Hismanal): antihistamine
Grepafloxacin (Raxar): antibiotic
Cisapride (Propulsid): caused GI problems
Which antibiotic can cause QT elongation problems?
erythromycin
When making an IV solution, what should you NEVER mix phenytoin with?
dextrose
use NS!
When making an IV, what should you never mix amphotericin with?
NS
When making an IV, what should you NEVER mix with opiates?
beta-lactams
What will physically and chemically react with the beta-lactam rings of penicillins, cephalosporins, and monobactams in an IV solution and cause decomposition?
gentamicin and other basic solution drugs like furosemide
What are some red flag hyperlipidemia drugs?
bile acid sequesterants
statins
What are some red flag drugs for GERD/ulcers?
cimetidine
cisapride
sucralfate
What is a red flag drug for osteoporosis?
alendronate
What are some red flag anticonvulsants?
carbamazepine
phenobarbitol
phenytoin
What is a red flag immunosuppressant?
cyclosporine
What is a red flag drug for CHF?
digoxin
What are some red flag drugs for TB?
isoniazid
rifampin
What is a red flag anticoagulant?
warfarin
What is a red flag asthma bronchodilator?
theophylline
What is a red flag herbal product?
St. John's Wort
What is a red flag drug for UTI?
quinolones
What are some red flag drugs for HIV/AIDS?
reverse transcriptase inhibitors
protease inhibitors
non-nucleoside reverse transcriptase inhibitors
What is a red flag women's product?
oral contraceptives
What is a red flag anti-depressant MAOI?
tranylcypromine (Parnate)
What is a red flag antibiotic?
erythromycin and other macrolides
What is a red flag manic-depressive drug?
lithium
What is a red flag anti-fungal drug?
itraconazole
What are "momma's little helpers"?
amphetamines and secobarbitol
What drugs are the main substrates for p-glycoprotein, ABC?
digoxin
fexofenadine
vincristine
indinavir
colchicine
topotecan
paclitaxel
loperamide
What drugs inhibit p-glycoprotein ABC?
ritonavir
cyclosporine
verapamil
erythromycin
ketoconazole
itraconazole
quinidine
azithromycin
valspodar
What drugs induce p-glycoprotein?
St. John's Wort
rifampin
Which drug is given to cancer patients to get a more effective absorption of anticancer drugs and inhibit p-glycoprotein?
verapamil
What are some drugs that are substrates for organic cation transporters (OCTs) drug transporters?
cimetidine
methotrexate
zidovudine
What are some drugs that are inhibitors of the OCT transporters?
probenicid
cefadroxil
cefamandole
cefazolin
Which (OCT) drug is given with penicillins/cephalosporins to increase their absorption when there is a severe infection?
probenicid
Which drugs (inhibitors of OCT) can block their own elimination?
cephalosporins
What are some known cardiovascular substrates for p-glycoprotein?
digoxin
diltiazem
nicardipine
verapamil
mostly calcium channel blockers
What are some known antineoplastic substrates for p-gycoprotein?
vinblastine
vincristine
etoposide
paclitaxel
What are some known transplant substrates for p-glycoproteins?
cyclosporine
tacrolimus
What are some steroid substrates for p-glycoprotein?