3. Biotransformation/Elimination Flashcards
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)
biotransformation water longer penicillin kidney liver small intestine glucoridination phase 2 toxic NAPQI glutothione n-acetyl cysteine irreversible
- 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)
feverall
excedrin
robitussin
ultracet
- 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
one hydroxyl two parent metabolite anti-platelet
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
24 85 CH3 12 OH 6 inctive
oversedation memory short metabolites high
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 --> \_\_\_\_
d-methyl codeine
CYP2D6
CYP2D6
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
HMG CoA Reductase inhibitor rhabdomyelisis erythromycin 2C9 low anaerobic warfarin fluconazole substrates St. Johns Wort
• 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
non-sedating anti-allergy torsades de pointes lidocaine cardio acid
Result of terfenadine toxicity:
• Rhabo - ____ dialysis needed (kidney tubules are clogged up)
renal
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
midazolam sedate orally small intestine oral
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
paroxetine
fluoxetine
setraline
serotinergic
serotonin
serotonin syndromes
• 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)
rifampin
warfarin
categories
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
50 ethanol norethindrone 7-8 99 antimicrobial
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
pulmonary dysentery nervous 24 12 pregnancies ethylene estradiol
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)
decdrease diazepam cirrhosis atypical cholinesterases daily ventilate receptor sensitivity receptor sensitivyt B2
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
benzo's methyl low oxazepam ethanol endogenous zero first 50 lidocoaine numb
Drug Excretion
- Number one organ is the ____. Also drug removed in feces, ____, breast milk.
- In kidney drugs that are still ____ soluble can be reabsorbed back into blood stream. Need biotransformation to decrease lipid solubility and speed up excretion.
- Typically get 1% of ____ levels in breast milk but that may be enough opioid (hydrocodone in Vicodin®) to cause ____ and ____ in breast feeding infant.
- All drugs are poisons
- Biotransformation sets up drugs for better excretion
- Just bc drug is in kidney tubule, that doesn’t mean its leaving, can still be lipid soluble and reenter the blood stream
- With breast milk > becomes an issue with breast feeding women; 1% of plasma levels in breast milk, but in a newborn baby > this can be enough of an opioid to casue a lot of sedation in the baby, but the baby can become constipated
kidney saliva lipid plasma sedation constipation
Lithium major drug in ____. Has ____ therapeutic index. Lithium accumulation due to concomitant ____ ingestion can cause kidney damage, tremors and seizures.
• Example of how played drugs entering kidney tubular system • WWII > penicillin has been isolated ○ A miracle drug ○ Excreted 99.5% unchanged; undergoes very little \_\_\_\_; actively pumped into kidney > collecting urine of soldiers and reisolating ○ Also gave \_\_\_\_ at same time of penicilling > blocked active secretion > kept penicillin around longer (give less) § Now today, the major use is in treatment of gout > uricoseric, increases excretion of uric acid in kdiney tubule system (during gout, have uric acid levels) • \_\_\_\_ - also actively secreted into renal tubular system - major bipolar drug ○ Involved in serious drug interactions - low TI (4x eff dose can be lethal) ○ \_\_\_\_ (precription and OTC) > block active secretion o flithium > buildup > lithium toxicity • How to know low TI (theo, warfarin) > \_\_\_\_ every month or so; with warfarin you're getting an \_\_\_\_; measure lithium blood levels and theophylline blood levels ○ Watch out for adverse drug interactions
bipolar disorder
low
NSAID
biotransformation
probenicid
lithium
NSAIDs
blood tests
INR
Playing with urine pH - Ion Trapping
Useful in treatment of overdoses of weak acids like ____ and ____. Alkalinize the urine with intravenous ____ to speed excretion of week acid.
* Aspirin and sedatives (barbituates - used for anxiety before the benzo's - but we morphed away bc they have a TI of 4-8, while benzo's have 20-100) * Both barbs and aspirins - weak acids - what can be done in a poisoning to ehance excretion, and alkynaize the urine (up the \_\_\_\_) give IV sodium bicarbonate * Uncharged, it can go right back into the BS > but once you up the pH it becomes \_\_\_\_ (\_\_\_\_) > so doesn't traverse back to the BS > ion trapped > more efficiently excrete * Give antagonists; to benzo's - \_\_\_\_; or to opioids - \_\_\_\_
aspirin barbiturates pH charged anionic flomazonale naloxone
Elimination Enzyme Kinetics
• Least common is ____ order elimination kinetics. More ____ than enzyme. Drug eliminated by ____ amount regardless of concentration. ____ after a drink or two is eliminated via zero order kinetics. Overdoses of drugs typically eliminated by first order kinetics can switch to ____ order kinetics because there is now more drug than enzyme. Overdose of ____.
* Kinetics depends on how efficient durg is \_\_\_\_, how readily \_\_\_\_ from kdiney * But zero order, not a lot of \_\_\_\_ to detoxify; eliminated by a constant amount regardless a concentration
zero drug constant alcohol zero acetaminophen metabolized excreted enzymes
Ethanol example of zero order elimination kinetics
You get drunk and blood alcohol is ____ gram % after consumption of alcohol. YOU ARE SMASHED!!!
* Every hour it goes down by \_\_\_\_% * On overdose, first order kinetic drugs can flip to zero order for a little while
- 20
0. 1
Elimination Enzyme Kinetics
• ____ order elimination most common especially with therapeutic doses of drug. Drug is eliminated by constant ____ or ____% on each half life. More ____, more eliminated per unit time.
• Take a dose of 400 mg ibuprofen. Average blood level is 50 ug/ml with a half life of 4 hours.
• Half-life = amount of time for drug levels of blodo to be rduced by 50% • 2 advil = 400 mg • When concentrations are higher, you have more \_\_\_\_, but still 50% • Gives algorithim to dose most drugs, and most durgs are dosed on their half life ○ Drug dosed every 4/6 hours = close to \_\_\_\_ in body
first percent 50 drug eliminated half life
Ibuprofen has T1/2 of 4 hrs. Average peak blood levels after 400 mg dose is ____ ug/ml.
With first order eliminiation drug if you dose on half life you reach steady state blood levels by ____ half-lives
• Dose on half life > we know that you will reach in 3/4 half-lifes = \_\_\_\_ state conc of drugs (equilibirum achieved) • Dose 1 - no ibuprofein • Peaksa t 50 mg/ml, then 4 hours down to \_\_\_\_ • Dose again, goes up 50 mg/ml > goes to \_\_\_\_ • At second half it drops to 37.5 • Dose again, it goes 87.5, drops to 44 • Dose again, it goes 94 drops to 47 • Dose again 97, drops to \_\_\_\_ • Midpoint between peak and trough > at 4th half life >steady state • Steady state doesn't mean \_\_\_\_ (here it does) ○ Dose with 40 instead of 400, it will reach steady state in 4 half lifes but the curve would be \_\_\_\_ ○ As long as the dose is \_\_\_\_ • Dose more frequently then every half life > itll go into \_\_\_\_ blood levels • Patient with severe infection > want to be at steady state in one half life > give a \_\_\_\_ > see with antibiotics (can go on with ibuprofen too, why chase pain?)
50 four steady 25 75 48 therapeutic lower constant toxic loading dose
This is known as giving a loading dose. On first dose give ____ the amount and then cut back to ____ dose on each T 1⁄2.
With loading dose you reach steady state in ____ T 1⁄2.
* 400 gives \_\_\_\_ mg/ml > 800 gives \_\_\_\_mg/ml * Loading dose > double dose on first dose, and cut back at regular dose at all other half lifes * Going back to normal concentration \_\_\_\_ the half life at that level
double normal one 50 100 maintains
