3. Biotransformation/Elimination Flashcards
1
Q
ACETAMINOPHEN CONVERSION SLIDE!!!
• There are some drug thats don't undergo \_\_\_\_ • Biotransformation becomes important because even if it doesn't totally inactivate the drug, it makes it less lipid soluble, more \_\_\_\_ soluble, and more readily excreted • without biotransformation, drugs would stay in our body \_\_\_\_ than we want • Some drugs do not undergo biotransformation, like \_\_\_\_ ◦ they are 99.5% excreted unchanged, so you better have good \_\_\_\_ function to get rid of those drugs • this is one of the structures I'd like you to recognize • That's Tylenol, Acetaminophen • One of the possible outcomes of biotransformation is that the drug goes from active to inactive • When we swallow Acetaminophen and it gets processed in the \_\_\_\_ and \_\_\_\_ (major organs of biotransformation), about 95% of it binds to this (points to top right structure) ◦ that's a glucose molecule with an acid group - that's \_\_\_\_ • Whenever you have a drug binding to a big endogenous molecule, we call that a \_\_\_\_ reaction ○ usually happen after phase 1 reactions, but not always ○ that typically inactivates the drug, but there are a few exceptions (morphine) • The other potential thing that can happen with a drug (2 different pathways), it is processed into a metabolite that is potentially \_\_\_\_ • CYP2E1 is one of the Cytochrome P450 isoforms • cytochrome P450 is one of the enzymes located in the small intestine and liver that do some of the initial tweaks in drugs that may not totally inactivate them but make them more readily excreted • one of the tweaks with acetaminophen with CY2PEI is that it can convert acetaminophen into this potentially hepatotoxic (liver damaging) metabolite \_\_\_\_ • Take a therapeutic dose of acetaminophen > any NAPQI formed gets scavenged by antioxidant - \_\_\_\_ (inactivates the NAPQI) • Overdose on tylenol (prescription opioid abuser) > the left pathway gets saturated > too much drug > only 70% now, and the rest goes to the toxic area > too much > irreversible liver damager ○ Antidote for acetaminophen overdose > \_\_\_\_ (mycomyst) ○ Once person is yellow, whatever damage is caused is \_\_\_\_ (look fine for 24-48 hours)
A
biotransformation water longer penicillin kidney liver small intestine glucoridination phase 2 toxic NAPQI glutothione n-acetyl cysteine irreversible
2
Q
- Someone with flu > ____ > contains acetomenophen, and for headache take ____; and for joint pain you’ll take ____
- Sometimes its clinicians, or its people self-medicating
- ____ - acetomenophen (-cet is telling you that)
A
feverall
excedrin
robitussin
ultracet
3
Q
- First step makes it less active
- Know the structures
- ASA > SA (phase ____ reaction) (acetyl to ____ group) > binds to AA/sugar acid (phase ____, inactivating it)
- Dosing on the combination of ____ and active ____
- SA is kinder to the stomach than aspirin > no more ____ activity
A
one hydroxyl two parent metabolite anti-platelet
4
Q
Diazepam Metbaolic Scheme
Diazepam (active T1/2 = ____ hours) (at 80 yrs old = ____ hours) > loses ____ > desmethyldiazepam (active, T1/2 = ____ hours) > add ____ > oxazepam (active, T1/2 = ____ hours) > glucuronic acid > ____
Consequences of benzodiazepine accumulation: ____,
Confusion, ____ Impairment
Strategy: Prescribe ____-acting benzodiazepine without active ____.
• Benzodiazepines \_\_\_\_ therapeutic index (30-50, need 50-fold OD to start killing people) ○ Mix with vodka > bad news • As we age ability to process drugs goes down (bc of liver/kidney function), and the half life increases, and the active metabolites prolongs the duration of the drug • Glucuronidation is the final step to inactivate
A
24 85 CH3 12 OH 6 inctive
oversedation memory short metabolites high
5
Q
Analgesic Prodrugs
* Prodrug - when initially swallow > no activity or not full activity * Codeine > \_\_\_\_ > active metabolite of codeine * 10-15% individuals are low on \_\_\_\_ * The issue with Codeine is that it's an opioid, but for it to be activated, it has to be de-methylated by one of these cytochrome p450 enzymes --> \_\_\_\_
A
d-methyl codeine
CYP2D6
CYP2D6
6
Q
CYP TABLE!
• Asterisk means potentially prescribed • Ends in -statin \_\_\_\_ ○ Generally well tolerated, but if they build up > cause myalgeis and muscle aches, and \_\_\_\_ > skeletal muscle breaks down, breaks down kidney tubules > acute kidney failure • \_\_\_\_ and Clarithrymycin can jack up blood levels of stain (so can grapefruit juice) • You don't want kids before a sedation with benzodiazepines drinking grapefruit juice because it can jack up blood levels of these • when kids get over-sedated, they obstruct, lose ability to maintain airway • Warfarin is a \_\_\_\_ substrate - \_\_\_\_ therapeutic index • Metronizadole is a great antibiotic against \_\_\_\_ infections (oral surgeons and periodontists like this drug) ○ don't do it with \_\_\_\_ ○ and don't do it with \_\_\_\_ (anti fungal drug - good for candida albicans infections) • These inducers (points to bottom row) will lower blood levels of the \_\_\_\_ ◦ If you are a woman taking oral contraceptives, problem with taking \_\_\_\_ will make the blood levels of estrogen and progestins go sub-therapeutic
A
HMG CoA Reductase inhibitor rhabdomyelisis erythromycin 2C9 low anaerobic warfarin fluconazole substrates St. Johns Wort
7
Q
• Large R group
• First ____ antihistamine
• Terfenadine for effectiveness > prodrug > converted in SI/liver by a CP450 isoform > fexofenadine (most of the ____effects)
• Erythromycin, clarithromcyin, grape fruit juice block formation
• Terfenadine has effects on heart > lethal form of ventricular arrythemias > ____ > shoot ____ in and it doesn’t work
○ Allegra is not ____ toxic
• Methyl to carboxylic acid; allegra is the ____-metabolite of seldane
A
non-sedating anti-allergy torsades de pointes lidocaine cardio acid
8
Q
Result of terfenadine toxicity:
• Rhabo - ____ dialysis needed (kidney tubules are clogged up)
A
renal
9
Q
Placebo/erthromcin 500 mg TID for 6 days followed by a single dose of oral midazolam (Versed) 6 mg
• In oral surgery patients, we are typically giving IV Erythromycin, titrating to effect • With kids, they are typically getting this orally • This study is showing if you put somebody on Erythromycin (major drug for penicillin-allergic individuals) for 6 days, and then you give them a single dose of oral midazolam (or put on sugar pill) the blood levels of \_\_\_\_ were 3 times higher than if they were on placebo • The issue is you can over \_\_\_\_ a kid • The Cytochrome P450 interactions are more likely to happen when one or both drugs are given \_\_\_\_ because a lot of the interference happens pre-hepatically in the \_\_\_\_ • \_\_\_\_ drugs will put a lot more drug into the small intestine than IV drugs
A
midazolam sedate orally small intestine oral
10
Q
Analgesic Prodrugs
• There are drugs that can block the activity of CYP2D6 and can block the conversion of the prodrug into the active metabolite • \_\_\_\_ (Paxil), \_\_\_\_ (Prozac), \_\_\_\_ (Zoloft) are SSRIs ◦ all 3 of these are in the top 50 selling drugs in US - for depression, anxiety, OCD • Tramadol has some intrinsic \_\_\_\_ activity already because its active metabolite stimulates mu-opioid or kappa-opioid receptors, but the parent molecule increases \_\_\_\_ levels • if you introduce other drugs that increase serotonin levels, can end up with \_\_\_\_ - tremors, seizures, potentially life-threatening • Not only blunting the analgesic effect of the drug
A
paroxetine
fluoxetine
setraline
serotinergic
serotonin
serotonin syndromes
11
Q
• Inducers
○ Speed up the metabolism of the substrate
○ ____ - have or been exposed to Tb (also used for lepersy)
§ Inducer of cyto P450 isoforms
§ Taken with a lot of other drugs, can drop levels of other drugs to subtherapeutic (with ____ - they stroke out)
• Oral contraceptives - exposed to Tb - put on rifampin (on for a long time)
• Cyto P450 mainly in SI and liver
○ Drugs can be substrates, inhibitors (jack up blood levels to toxic levels) or can be inducers (increase amount of enzymes that metbaolize substrates)
§ Drugs can fit into multiple ____ (substate of one, but inihibiotr of a another)
A
rifampin
warfarin
categories
12
Q
Rifampin
• Blood levels of estorgen component of oral contrapceptiv when on rifampin; blood levels when taken off • Down by \_\_\_\_% when on rifampin • Both the ethanol \_\_\_\_ and the other component (\_\_\_\_ - progestin) • Even with \_\_\_\_ people - you can clearly show that this sig reduced blood levels • Over \_\_\_\_% certain that this effect is real • Only \_\_\_\_ that reduces blood levels and effectivess or oral contraceptives ○ Warning of other antibiotics
A
50 ethanol norethindrone 7-8 99 antimicrobial
13
Q
St John’s Wort and Oral Contraceptives
Used in all ____ complaints, bladder troubles, in suppression of urine, ____, worms, diarrhea, hysteria and ____ depression, hemoptysis and other hemorrhages and jaundice
• Oral contraceptive once a day; half-life = \_\_\_\_ hours • St John's wort • When on placebo - 24 hours • When on st. johns - \_\_\_\_ hours; decreasing the time that the oral contraceptive blood levels are in therapeutic range > unexpected \_\_\_\_ in women taking SJW ○ Considered a food product • \_\_\_\_ inhibits ovulation
A
pulmonary dysentery nervous 24 12 pregnancies ethylene estradiol
14
Q
Factors affecting biotransformation
- As we age pre-hepatic and hepatic enzymes for certain drugs ____. This can lead to drug accumulation. Example I’ve given you already is ____ (Valium®).
- Liver damage (____) will decrease metabolism of many drugs
- Genetics - deficiency in key enzyme that metabolizes drug – ____ and succinylcholine (Anectine®)
- Enzyme inhibitors or inducers on board• More of a problem if dosing ____
○ Valium opens up Cl > hyperpolarization, makes GABA work better
○ Drug has active metabolites where they’re also active, the biotrasnformation also gets delayed
• Succinylcholine - nicotinic M cholinergic blocking agent > chewed up very quickly; some patients have an atypical enzyme where it’s not readily chewed up and remains > muscle paralysis, inc intercostal muscles where you have to ____
• Inc ____ ot CNS depressents (op’s, benzo’s) > can get a bigger bang of buck
• Drugs that inetact with beta receptors; as we get older we have decreased ____ (like ____ for asthma)
A
decdrease diazepam cirrhosis atypical cholinesterases daily ventilate receptor sensitivity receptor sensitivyt B2
15
Q
Effects of Age on Hepatic Clearance of Some Drugs
• Blue = \_\_\_\_ > differ with duration and potency • Theophylline - turbo-harged caffeine > very involved in serious adverse effects > one \_\_\_\_ group change from caffeine > involved with drug interactions bc of \_\_\_\_ TI ○ If have a high TI > double blood levels bc it doesn't matter • Metabolite of diazopam > \_\_\_\_ • \_\_\_\_ metabolism is very slow, so doesn't change as we get older • Phase II > binding big \_\_\_\_ molecule • At low doses > ethanol is eliminated at \_\_\_\_ order kinetics (constant amount is eliminated per hour); most drugs are \_\_\_\_ order (\_\_\_\_% on each half half) • Kidney function can change as age, so \_\_\_\_ can stay around body longer (won't be \_\_\_\_ longer tho); has to do with how long it stays at site, not metabolism
A
benzo's methyl low oxazepam ethanol endogenous zero first 50 lidocoaine numb
