Drugs to Recognize Exam I (August 15) Flashcards
Carbamazepine
3A4 inducer
induces 2C9 and 2C19
-induces enzyme responsible for its own metabolism, reducing levels of active drug over time
Prodrug (Prodrugs are inactive compounds that are metabolized in the body to their active forms)
Rifampin
induce 3A4
induce 2C9 and 2C19
induces P-gp/MDR1 transporters (gut kidney liver efflux) increase drug efflux and decrease drug plasma conc
Phenytoin
induce 3A4
zero-order kinetics of eliminations
restrictive hepatic clearance/low hepatic extraction (Q greater than f x CLint)
Little “first pass metabolism” when given orally. A change in binding or drug metabolism/excretion activity will have a greater effect on hepatic clearance than changes in liver blood flow. Capacity-limited clearance.
Phenobarbital
induce 3A4
induce 2C9 and 2C19
St. John’s wort
induces 3A4
induces P-gp/MDR1 transporters (gut kidney liver efflux) increase drug efflux and decrease drug plasma conc
grapefruit juice
will bioavailability or half life be affected?
inhibits 3A4 in enterocytes (intestinal)
not hepatic 3A4
affects bioavailability NOT half life
Clarithromycin
strong inhibitor of 3A4
3A4 catalyzes both hydroxylation and N-demethylation of Clarithromycin
Ritonavir
strong 3A4 inhibitor
anti-HIV protease inhibitor
significant GI adverse effects limit its critical use; low dose has no GI effects but potently inhibits 3A4
chemicals in cigarette smoke, charboiled food, cruciferous vegetables
induce 1A2 3 fold
smokers sometimes need higher doses of certain drugs metabolized by CYP1A2
A patient presents with severe broken leg and is in extreme pain; you prescribe x amount of codeine but thirty minutes later is still writhing in pain; you double check the dose and that it was administered but there were no errors. What might explain this?
drug isn’t working
-codeine is a Prodrug
-patient has variant allele of 2D6 - could lead to poor metabolize and consequently decreased efficacy and lack of sedative effect
N-acetyl benzoquinoneimine
this is a highly reactive metabolite generated from acetaminophen when phase II enzymes are saturated; usually is conjugated by glutathione; if glutathione is depleted then hepatotoxicity ensues
sulfonamides
Sulfonamides may compete for protein binding and increase the unbound fraction of other drugs.
adding sulfonamide will increase distribution of other drug
Warfarin
zero order kinetics of elimination
restrictive hepatic clearance/low hepatic extraction (Q greater than f x CLint)
Little “first pass metabolism” when given orally. A change in binding or drug metabolism/excretion activity will have a greater effect on hepatic clearance than changes in liver blood flow. Capacity-limited clearance.
patients with 2C9*2 or *3 have decreased metabolic inactivation of S warfarin (most potent form); increased conc. of active warfarin with standard dose; prone to experiencing bleeding events; patients require lower warfarin dosing
lidocaine
exhibits NON-RESTRICTIVE HEPATIC CLEARANCE (Q is less than f x CLint)
Hepatic clearance is sensitive to changes in liver blood flow and less sensitive to alterations in binding or intrinsic clearance. Flow-dependent clearance: conditions that reduce hepatic blood flow (CHF, hypotension) will reduce hepatic clearance.
propranolol
exhibits NON-RESTRICTIVE HEPATIC CLEARANCE (Q is less than f x CLint)
Hepatic clearance is sensitive to changes in liver blood flow and less sensitive to alterations in binding or intrinsic clearance. Flow-dependent clearance: conditions that reduce hepatic blood flow (CHF, hypotension) will reduce hepatic clearance.
morphine
Phase II reactions will activate drug
(exceptions bc for most drugs Phase II inactivates)
ex of a parental drug that contains –OH, -COOH or –NH2 functional groups and can directly undergo Phase II metabolism without prior phase I metabolism
minoxidil
Phase II reactions will activate drug
exceptions bc for most drugs Phase II inactivates
Isoniazid
ex of a parental drug that contains –OH, -COOH or –NH2 functional groups and can directly undergo Phase II metabolism without prior phase I metabolism
Irinotecan
Prodrug
Codeine
Prodrug
Prednisone
Prodrug
Glucocorticoids
induce 3A4
Fluconazole
Ketoconazole
Itranaconazole
inhibits 3A4
Ritonavir
inhibits 3A4
Erthyromycin
inhibits 3A4
Cyclosporin
3A4 substrate
(immunosuppressant drug to prevent organ rejection)
potent inhibitor of OATP1B1 and blocks statin uptake
INHIBITS P-gp/MDR1 transporters in gut kidney and liver (decreased drug elimination and increased drug plasma conc)
elderly
decreased renal function
decreased activity of Phase I metabolism
chloramphenicol
given to babies (who have conjugating enzyme deficiency) will lead to build up of chloramphenicol oxidation metabolite which will result in gray baby syndrome and circulatory collapse and cyanosis
pregnancy
some enzymes (2C9 2D6 and 3A4 increase) with others decrease (1A2, C219)
alcohol
induces expression of 2E1
pollutants and xenobiotics
induce specific p450 enzymes
Disease
effect liver or blood flow to liver (cardiac disease)
inflammatory cytokines
decrease expression of many CYP450 isoforms
Probenecid
potent inhibitor of OAT1
Probenecid prevents
Nephrotoxicity by blocking OAT1-dependent
Cidefovir uptake
into the proximal tubules
great for preventing renal toxcitiy w Cidefovir… but now all OAT1 transporters inhibited… (can have effects on other drugs that utilize OAT1 elsewhere)
Cidefovir
- anti-viral used to treat CMV retinitis
- transported into proximal tubules by OAT1
- treatment limited by severe renal toxicity
- Cidefovir always co-administered with probenecid bc it blocks uptake into the renal epithelium
- will still be cleared eventually but this time through Glomerular filtration not through transport across renal epithelium
Statins
OATP1B1 transport
(BCRP efflux)
SNP in OATP1BI influence STATIN efficacy and systemic exposure
OATP1B1*5 and 15 have decreased transporter activity; decreased STATIN uptake and efficacy; increased systemic statin exposure and increased statin toxicity
(15 most commonly reduced in Caucasians, Asians, then African Americans)
(Cyclosporin is potent inhibitor of OATP1B1 and blocks statin uptake)
Statin in muscle causes myopathy and rhabdomyolysis
metformin
very basic anti-diabetic drug that acts in the liver and is eliminated unchanged by renal tubular excretion
(OCT/MATE SNPs result in loss of transporter activity and decreased kidney uptake/excretion so increased systemic drug availability)
cimetidine
histamine H2 receptor antagonist used to treat acid peptic disorder (eliminated extensively via kidney)
mediates lots of OCT/MATE interactions
prevents renal elimination of other OCT dependent drugs
-administered w Cisplatin and prevents Cisplatin-induced nephrotoxicity
(non-selective inhibitor of several p450 isoforms)
Cisplatin
chemotherapeutic agent to treat certain cancers
-use limited by nephrotoxicity
Co-administration of CIMETIDINE blocks Cisplatin uptake into the kidney and prevents Cisplatin-induced nephrotoxicity
(primarily eliminated via renal tubular excretion)
BBB
- tight junctions prevent ions and large molecules passing between endothelial cells
- ABC transporters expressed on endothelial cells of BBB (P-gp/MDR1 BCRP MRP family efflux pumps)
- prevent access of xenobiotic compounds (drugs) to the CNS
- will exclude most drugs other than those small (less than 400Da and lipophilic)
P-gp1/MDR1 (cancer connection)
- tumor cells often “upregulate” expression of P-gp/MDR1
- increased expression of P-gp/MDR1 in tumor cells is associated with a more aggressive phenotype, poorer prognosis and decreased sensitivity to chemotherapeutic drugs
- increased expression of P-gp/MDR1 in tumor cells promotes efflux of anti-cancer drugs
Through what transporter will glutathione, glucuronide and sulfate conjugates be excreted?
MRP
Loperamide
opiod receptor agonist used to treat diarrhea
substrate for P-gp and does not cross BBB
Co administration w cyclosporin (P-gp inhibitor) allows Loperamide to cross BBB and can cause respiratory depression
CYP2D6, 2C9 and 2C19
polymorphic
together they metabolize approx 50% of the 200 most commonly used drugs
- significant variation in enzyme activity between individuals
- polymorphisms are clinically significant
(2D6) Significant polymorphisms and levels of enzyme activity between ethnic groups
2C191
2C192 and 3
2C1917
- 1 normal
- 2 and *3 non functional
- 17 increased expression/increased activity
2C9*2 and *3
2C9*15 and *25
- 2 and *3 reduced function variants
- 15 and *25 null variants
2C9*2 or *3 have decreased metabolic inactivation of S warfarin (most potent form); increased conc. of active warfarin with standard dose; prone to experiencing bleeding events; patients require lower warfarin dosing
VKORC1
direct target of warfarin
common polymorphism is 1639 G to A
G is associated with higher VKORC1 expression and a higher warfarin dose
A is associated with lower VKORC1 expression and a lower warfarin dose needed
(90% Asians carry A allele, 37% whites, 14% Africans)
Rare mutations in the VKORC1 coding region are associated with warfarin resistance (reduced affinity) that require v. high doses of warfarin to achieve anticoagulation
OATP1B1*15
polymorphisms in drug transporters causing elevated drug levels
OATP1B1*15 results in increased statins and increased risk of myopathy
HLA-B*1502
Carbamazepine-induced Steven Johnson Syndrome in Han Chinese
FDA recommends Pharmacogenetic testing to be used to screen Asian patients requiring carbamazepine in order to avoid SJS
Drug-induced hypersensitivity reactions
(Allergic-like reactions, often life threatening)
Trastuzumab (Herceptin)
an anti-Her2/ErbB2 monoclonal antibody used to treat breast cancer in patients whose tumor overexpresses the Her2/ErbB2 receptor
Imatinib (Gleevac)
a tyrosine kinase inhibitor specific for the BCR-ABL Chr breakpoint oncoprotein found in patients with Chronic Myeloid Leukemia
Gefitnib (Iressa)
an EGFR tyrosine kinase inhibitor used to treat a subset (10-20%) of Non-Small cell lung cancers patients that harbor the L858R activating mutation in their EGFR
Ritonavir
potent 3A4 inhibitor
anti-HIV protease inhibitor
-significant GI adverse effects limit its use clinically
(low doses of Ritonavir has no GI effects but potentially inhibits 3A4 so will decrease first pass metabolism of Lopinavir “boosting” its levels -enhanced anti-HIV effect
Ethanol/chronic alcohol
induce p450 enzymes
- chronic alcohol induces expression of CYP2E1
can result in N-acetyl benzoquinoneimine metabolite from acetaminophen
higher first pass metabolism in men than women
What is tachyphylaxis?
rapid development of tolerance to drug’s effects
describes the rapid development of diminished responsiveness to a drug.
