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62 Cards in this Set
- Front
- Back
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What drugs does CYP1A1/2 metabolize?
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Theophylline
Caffeine (R)-warfarin |
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What drugs induce CYP1A1/2?
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Smoking
Charcoal-grilled meat Rifampin Carbamazepine Omeprazole |
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What drugs inhibit CYP1A1/2?
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Fluvoxamine
Fluoroquinolones |
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What is the probe/test for CYP1A1/2?
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Caffeine [Urine, Breath]
3-demethylation |
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What drugs does CYP2C9 metabolize?
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NSAIDS
Phenytoin Tolbutamide (S)-warfarin |
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What drugs induce CYP2C9?
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Ethanol
Rifampin Carbamazepine |
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What drugs inhibit CYP2C9?
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Amiodarone
Fluvastatin Fluconazole |
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What is the probe/test for CYP2C9?
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Tolbutamide [Urine]
(S)-warfarin [Urine] 7-hydroxylation |
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In what populations is there decreased activity in CYP2C9? And by what %?
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-1-3% in Caucasians
-3% in African Americans |
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What drugs does CYP2C19 metabolize?
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Benzodiazepines
TCAs Omeprazole Citalopram |
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What drugs induce CYP2C19?
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Rifampin
Carbamazepine |
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What drugs inhibit CYP2C19?
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Fluvoxamine
Fluoxetine Ticlopidine |
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What is the probe/test for CYP2C19?
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Omeprazole [Urine]
4-hydroxylation |
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In what populations is there a decreased activity of CYP2C19 and by what %?
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-2-5% in Caucasians
-15-20% in Asians |
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What drugs does CYP2D6 metabolize?
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TCAs
Antiarrythmics B-blockers Debrisoquine Nortriptyline Codeine* --> Morphine |
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What drugs inhibit CYP2D6?
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Fluoxetine
Quinidine |
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What is the probe/test for CYP2D6?
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Debrisoquine [Urine]
4-hydroxylation Dextromethorphan [Urine] O-demethylation |
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In what populations is there a decreased activity of CYP2D6 and by what %?
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-5-10% in Caucasians
-1-3% in Chinese and African Americans |
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What drugs does CYP2E1 metabolize?
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Acetaminophen --> Toxic metab
Ethanol CCl4 |
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What drugs induce CYP2E1?
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Alcohol (Chronic)
Tobacco |
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By what mechanism is CYP2E1 induced?
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Protein stabilization (aka decreased protein degradation)
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What drugs inhibit CYP2E1?
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Disulfuram
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What is the probe/test for CYP2E1?
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Chlorzoxazone [Urine]
6-hydroxylation |
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What drugs are metabolized by CYP3A4?
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Statins
Midazolam Diazepam --> Active metab Terfenadine* (R)-warfarin Cyclosporine |
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What drugs induce CYP3A4?
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Phenytoin
St. John's Wort Rifampin Carbamazepine Glucocorticoids Phenobarbital |
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By what mechanism is CYP3A4 induced?
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-Activation of PXR
-PXR forms heterodimer w/ RXR -Functions as a transcription factor for 3A4 -Protein synthesis is stimulated |
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What drugs inhibit CYP3A4?
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Ketoconazole
Erythromycin Grapefruit Juice |
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What is the probe/test for CYP3A4?
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Midazolam [Blood]
(1-hydroxylation) Erythromycin [Breath] (N-demethylation) |
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What is CYP3A4 primarily responsible for?
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1st pass metabolism
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What is different about Pravastatin, as compared to the other statins?
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Does not need to undergo metabolism, but rather is eliminated unchanged (renal excretion)
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What's the issue with St. John's Wort?
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If you take oral contraceptives with St. John's Wort, leads to an increased metabolism of oral contraceptives and thus increased failure rates of oral contraceptives.
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Irinotecan (Captosar) is metabolized by....
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UGT1A1
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Polymorphisms in UGT1A1 (which metabolizes Irinotecan) results in ADRs including:
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Neutropenia
Profound diarrhea Myelosuppression |
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What are the 2 problematic alleles for (S)-warfarin
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CYP2C9*2
CYP2C9*3 |
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What % of caucasians have the two problematic alleles for (S)-warfarin?
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CYP2C9*2 - 10-20%
CYP2C9*3 - 6-10% |
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Is there an issue with warfarin in the elderly?
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Warfarin is highly bound to albumin and in the elderly, there is decreased binding, which results in a greater % of free, pharmacologically active drug
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What's the issue with propanolol in the elderly?
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Due to a decrease in first pass metabolism, giving this drug in normal doses in the elderly can result in increased plasma concentrations of the drug.
Also, propanolol is fat-soluble, and the elderly have higher amounts of fat. |
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What allele do rapid caffeine metabolizers have?
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Homozygous for CYP1A2*1A allele
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What allele do slow caffeine metabolizers have?
What problem may occur in this population? |
Carriers of variant CYP1A2*1F allele
Increased risk of MI |
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What is Trastazumab (Herceptin) used for?
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Metastatic breast cancer whose tumor over expresses the HER2 protein
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Name 4 changes in body composition that occur in the elderly
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1. Decreased lean body mass
2. Increased fat 3. Decreased plasma volume 4. Decreased total body water |
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What is the result of having greater amounts of fat in the elderly?
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Can lead to increased accumulation and possible toxicity of fat-soluble drugs
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Name 5 changes in the gastrointestinal tract that occur in the elderly
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1. Decreased secretions
2. Slight decrease in absorption 3. Decreased active transport 4. Decreased GI peristalsis 5. Decreased rate of stomach emptying |
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Name 3 changes in hepatic drug metabolism in the elderly
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1. Decreased size
2. Decreased liver blood flow 3. Decreased drug metabolism |
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Name 5 changes in the kidneys that occur in the elderly
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1. Decreased # of functioning nephrons
2. Decreased glomerular filtration rate 3. Decreased renal blood flow 4. Decreased creatinine clearance 5. Decreased tubular max. of many substances |
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Name the results of drug toxicity in elderly individuals w/ diminished renal function after being given the following drugs
-Aminoglycosides -Oral antidiabetics -Digoxin -NSAIDS -Anticholinergics |
-Aminoglycosides - Deafness & kidney toxicity
-Oral antidiabetics - Hypoglycemia -Digoxin - Vomiting and irregular heartbeat -NSAIDS - Renal failure -Anticholinergics - Confusional states |
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Name 8 cardiovascular changes in the elderly
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1. Decreased baroreceptor reflexes
2. Decreased blood vessel resiliency 3. Increased thickness of vessels 4. Increased predisposition to orthostatic hypertension 5. Decreased response to B-adrenergic stimulation 6. Increased peripheral resistance 7. Slight decrease in cardiac output 8. Decreased perfusion to organs (kidneys & liver) |
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Name 7 central and autonomic nervous system changes in the elderly
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1. Decreased B-adrenergic responses
2. Decreased muscarinic receptor responses 3. Decreased cerebral blood flow 4. Decreased ST memory 5. Decreased coordination 6. Increased susceptibility to drug-induced confusion, loss of balance, and cognitive impairment especially w/ drugs that reduce blood pressure (antihypertensives, diuretics, sedatives, phenothiazines, antidepressants) OR reduce plasma volume (diuretics) 7. Increased susceptibility to drug-induced sedation or confusion especially w/ drug acting on the CNS (sedatives, antihistamines, anticholinergics, H2-blockers, centrally acting antihypertensives) |
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8 Drugs/Classes to avoid in most instances in the elderly
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-Anticholinergic tricyclic antidepressants (amitryptyline and imipramine)
-Chlorpropamide (Diabenese) -Diphenhydramine (Benadryl) -Flurazepam (Dalmane) -Long-acting benzos (Diazepam) -Long-acting NSAIDs (Feldene) -Meperidine (Demerol) -Pentazocine (Talwin) |
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When considering giving a patient 6-MP for ALL, which enzyme should be tested for polymorphisms?
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TMPT
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CYP's with <40% sequence similarity are from...
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DIFFERENT families
Ex. 1A1 & 3A4 |
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CYP's with 40-60% sequence similarity are from...
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SAME family
DIFFERENT subfamily Ex. 2C9 & 2E1 |
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CYP's with >60% sequence similarity are from...
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SAME family
SAME subfamily Ex. 2C9 & 2C19 |
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Name two CYP families that are involved in cholesterol metabolism
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CYP7
CYP27 |
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Name 6 characteristics of metabolic probes
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-Specific metabolism (not metabolized by multiple P450s)
-Excreted in urine or saliva -Levels correlate w/ CYP activity -Not inhibitory to other enzymes -Safe; risk is minimal -Sensitive quantitative measures |
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Which isomer of warfarin is more potent - R or S?
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S(-) warfarin is more potent
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Explain the timing of inhibition
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-Rapid
-Within hours or same day -Offset is similar |
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Explain the timing of induction
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-Max. usually 1 week
-New proteins (drug metabolizing enzymes) need to be synthesized -Offset similar (have to wait for enzyme turnover) |
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Explain the mechanism of induction for CYP1A1
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-Activation of cytosolic AhR
-Translocated to nucleus by Arnt -Complex functions as a transcription factor for CYP1A -Protein synthesis is stimulated |
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Which CYP is Tamoxifen metabolized by?
What is Tamoxifen used for? Which allele of this enzyme causes women to have poorer treatment outcomes? |
-Tamoxifen is a pro-drug that is converted to endoxifen (active metabolite) by CYP2D6
-Used to treat breast cancer -CYP2D6*4 (poor metabolizers) have poorer breast cancer treatment outcomes |
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What are the ADRs associated w/ polymorphism's in TPMT?
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-Myelotoxicity
-Treatment related 2nd tumors |
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Example of prospective genotyping
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-Can predict TPMT status in almost 95% of patients
-Used to maximize efficacy and minimize toxicity |
