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71 Cards in this Set
- Front
- Back
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Genetic Polymorphism
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Distinct population differences apparent in expression or activity of isoenzymes
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Cytochrome P450 System
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Group of heme-containing enzymes involved in oxidative metabolism of a number of different drug classes, as well as endogenous substances, such as steroid hormones, fatty acids & prostaglandins.
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Distribution sites of P450 System
Name the major sites and other sites |
Major sites = liver & small intestine
Other sites = Gut wall Brain Epithelial Cells Lung tissue Kidney Placenta Ovaries |
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Nomenclature for naming isoenzymes: 3 tier classification system
Differentiate between Family, Genus, and Individual gene or species |
example CYP3A4
Family = 3 Genus = A Species = 4 |
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Name the 5 major Isoenzymes
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CYP3A4
CYP2D6 CYP1A2 CYP2E1 CYP2C FAMILY (2C9, 2C10, 2C19) |
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What is a substrate?
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Drug whose metabolism or biotransformation is catalyzed by an enzyme in the P450 family.
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What is an enzyme Inhibitor?
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Drug that inhibits the metabolism of another drug by an enzyme in the P450 system.
-Once inhibitor drug is cleared from system, inhibition ceases. -Most often occurs as a result of competitive binding at the enzymes binding site (competitive inhibition). This depends upon affinity of substrate for enzyme being inhibited, concentration of substrate required for inhibition, half-life or time to steady state of inhibitor drugs -less commonly occurs as a result of noncompetitive binding (Noncompetitive inhibition); which can occur as a result of inhibitor inactivation of the enzyme with normal substrate binding |
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What is Competitive Inhibition?
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Most often occurs as a result of competitive binding at the enzymes binding site
This depends upon affinity of substrate for enzyme being inhibited, concentration of substrate required for inhibition, half-life or time to steady state of inhibitor drugs |
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What is noncompetitive inhibition?
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less commonly occurs as a result of noncompetitive binding
-This can occur as a result of inhibitor inactivation of the enzyme with normal substrate binding |
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What is the enzyme Inducer?
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Drug that increases production of the enzymes responsible for the metabolism of other drugs, thus accelerating the clearance of those drugs.
This induction occurs when hepatic blood flow is increased, or synthesis of more CYP450 enzymes is stimulated -The time course of drug interaction dependent upon t1/2 of inducer -Enzyme induction influenced by age & liver disease (ability to induce drug metabolism may decrease with age, cirrhosis, hepatitis) |
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CYP3A4 general information
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-Broadest range of drugs/endogenous compounds (~50% of prescribed drugs)
-no evidence of genetic polymorphism -drug interactions associated w/ life-threatening arrhythmias |
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CYP3A4 SUBSTRATES drugs
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Benzodiazepines
CCB Carbamazepine Dexamethasone Erythromycin Ketoconazole Lovastatin Nefazodone Sertraline Venlafaxine Protease Inhibitors R-warfarin |
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CYP3A4 INHIBITORS drugs
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Antidepressants (Nefazodone>Fluvoxamine > Fluoxetine > Sert/Parox/Venla)
Azole antifungals (Keto>Itra>Flu) Cimetidine Clarithromycin Diltiazem Erythromycin GRAPEFRUIT JUICE Protease Inhibitors Voriconazole |
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CYP3A4 INDUCERS drugs
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Carbamazepine
Dexamethasone Phenobarbital Phenytoin Rifampin |
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CYP2D6 general info
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-Exhibits genetic polymorphism
-Poor metabolizers vs Extensive metabolizers -Poor metabolizers *7-10% of whites *Inc risk of drug accumulation/toxicity *Less therapeutic response to drugs that require active metabolite for activity *Relatively protected from drug interactions due to low 2D6 activity (2D6 inhibitors have little effect so inhibition does not reduce the metabolism further) -Extensive Metabolizers *Individuals w/ normal cyp2D6 activity (rest of the population) *more susceptible to drug interactions (basal enzyme activity is high & an inhibitor can produce a large decrease in substrate clearance) |
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CYP2D6 SUBSTRATES examples
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Antidepressants (TCA, SSRI)
Antipsychotics Beta Blockers Narcotics |
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CYP2D6 INHIBITOR examples
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Amiodarone
Antidepressants Cimetidine Fluphenzine Antipsychotics Quinidine |
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CYP2D6 INDUCERS examples
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Carbamazepine
Phenobarbital Phenytoin Rifampin Ritonavir |
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CYP1A2 general information
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-only P450 isoenzyme affected by TOBACCO
-Cigarette smoking can result in <3 fold increase in CYP1A2 activity (cig smoke acts like an inducer, and has an interaction w/ theophylline by inducing the metabolism of it) |
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CYP1A2 SUBSTRATES examples
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Antidepressants (TCA)
Clozapine Propranolol R-warfarin Theophylline Tacrine |
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CYP1A2 INHIBITORS examples
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Fluvoxamine
GRAPEFRUIT JUICE Quinolones (cipro > Enox > Norflox > Oflox >Lomeflox) |
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CYP1A2 INDUCERS examples
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Omeprazole
Phenobarbital Phenytoin Rifampin Smoking Char-broiled meat |
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CYP2E1 general info
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-inducible by ETHANOL
-responsible in part for metabolism of ACETAMINOPHEN -ethanol dependent persons may be at increased risk for APAP hepatotoxicity due to ethanol induction of CYP2E1 |
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CYP2E1 SUBSTRATES, INHIBITORS, INDUCERS examples
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SUBSTRATES
Acetaminophen Ethanol INHIBITORS Disulfiram INDUCERS Ethanol Isoniazid |
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CYP2C family general information
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-2C9, 2C10, 2C19, OTHERS
-2C19 exhibits genetic polymorphism -Poor metabolizers = 20% asians & African americans; 3-5% Whites |
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CYP2C family SUBSTRATES examples
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NSAIDs
Phenytoin S-Warfarin Torsemide Diazepam Losartan Amitriptyline Clomipramine Imipramine Omeprazole Tolbutamide Topiramate |
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CYP2C family INHIBITORS examples
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Azole antifungals (keto, itra, flu, vori)
Amiodarone Chloramphenicol Cimetidine Metronidazole Ritonavir Fluoxetine Fluvastatin Fluvoxamine Isoniazid Sertraline Omeprazole Topiramate Zafirlukast |
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CYP2C family INDUCERS examples
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Carbamazepine
Phenobarbital Phenytoin Rifampin |
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Grapefruit Juice
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-interaction discovered by accident (used to disguise taste in drug trial)
-primarily inhibits the activity of CYP3A4 *50% of drugs prescribed *particularly effects 1st pass metabolism -partly irreversible; enzyme does not return to normal immediately after moving through intestine -recovery half-life (after 1 glass) is ~1 day (after 3 days little effect remains) -amount consumed effects magnitude (varies between specific juice product) -avoid w/ "NTI" drugs *Amiodarone *Carbamazepine *Cyclosporine *Sirolimus *Tacrolimus -for other drugs, limit intake to 8 oz or 1/2 grapefruit per day |
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What are the most common cause of preventable ADRs?
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Drug interactions
Drug toxicity Dosing errors |
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What medications are most commonly associated w/ preventable ADRs?
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Warfarin
Digoxin Morphine |
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Why is Adverse Drug Reactions important?
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purpose is to enhance current understanding of adverse effects and try to PREVENT them from happening.
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Normal cardiac Output
Values |
Typical Distribution:
-Kidneys receive 20% blood flow (bf) -Splanchnic organs 20% bf -Liver receives 10% of bf -Muscle receives 15% of bf -Heart receives 5% of bf -Brain receives 15% of bf -Rest of body receives 15% bf |
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CHF
Cardiac Output |
-Decrease in overall CO (~50%)
-Body redirects blood flow (bf) for survival & increases it to vital organs: *less bf to kidneys *less bf to splanchnic organs mainly GI & some liver *Increase bf to heart *increase bf to brain |
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CHF
Absorption |
-in CHF there is decrease in gastric emptying (this leads to decrease in rate of absorption of some drugs)
-decrease in blood flow to muscles -decrease in absorption from IM injections important since some may not be able to take PO doses esp after surgery or intubation. -ex: *Phenytoin precipitates in to crystallized substance & is not absorbed well *digoxin & diazepam are poorly solubilized *use different administration route |
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CHF
Distribution |
-Decrease in volume of distribution
-more interstitial fluid volume, lower central volume of distribution -results in increase concentration of drugs after the loading dose -central Vd can drop & loading doses may change - need to use lower doses (ie amiodarone) |
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CHF
Metabolism |
-Decrease in hepatic blood flow
-Increase in hepatic congestion -this effects MORE MEDS than the effects on the kidneys |
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CHF
Clearance/Elimination |
-Decrease in clearance of some drugs
-Longer half life |
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CHF
Effects on Diuretics: FUROSEMIDE |
-lower peak concentrations
-absorption is incomplete (so lower conc) -response is blunted (goes to liver to be metabolized) -IV is more effective in CHF -larger doses recommended (very high, seen up to 300mg) -better to admin by IV since it doesn't rely on absorption |
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CHF
Effects on Diuretics: BUMEX |
-lower peak concentrations
-longer absorption time (so must wait longer to see effect; ~10-50mins) |
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CHF
Effects on Diuretics: HYDROCHLOROTHIAZIDE |
-INCREASE in half life (so can use lower doses and NEVER use alone; use in combo w/ loops)
-plan = use lower doses in severe CHF |
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CHF
Effects on Diuretics: METOLAZONE |
-increase 1/2 life
-increase in Vd -no change in clearance -plan = usually pts will tolerate this -use in combo w/ loop, seen more of this in CHF |
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CHF
Effects on DIGOXIN |
-use for CHF & AFib
-decrease in peak serum concentrations (4.25 vs 6.71 mcg/L) -time to peak prolonged (3.1 vs 1.2 hours) -decrease in total clearance -can develop TOXICITY (may take up to a week to see toxicity; be able to recognize S/S such as N/V) -plan = reduce dose 1/3-1/2 for what we would use for Afib (also imp if there is renal impairment) |
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CHF
Effects on NITRATES |
-impaired hepatic clearance
-nitrates will buid up in a system resulting in no nitrate free period leading to break through chest pain -Dinitrate needs liver metabolism -can try to cut dose down if taking large dose -better to switch to PO sustained NTG; doesn't have to be metabolized & won't last as long in the system (qAM & noon) -may develop tolerance since active nitrates stay around longer |
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CHF
Effects on PRAZOSIN (Minipress) |
-decrease in hepatic clearance
-see an increase in AUC -plan = decrease dose -not used as much; flomax which is similar to prazosin with how it is handled in the body; don't need as high a dose if have CHF; take QOD instead of QD |
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CHF
Effects on AMRINONE (Inamrinone) -this is a phosphodiesterase enzyme inhibitor -used for short term therapy in pts w/ intractable heart failure |
-Decrease in clearance (15 vs 23 L/hr for healthy volunteers)
-Half life increased (2.6 vs 3.6 hrs) -Plan = Dosing based on response of the pt -use in acute, increase CO w/out causing arrhythmias, start low |
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CHF
Effects on ANTIARRHYTHMICS -Lidocaine -Procainamide -Quinidine |
-Decrease in Vd
-Decrease in Clearance -Higher peak concentrations -Half life doubles -Plan = reduce doses to avoid toxicities; start low & titrate up slowly esp for atrial arrhythmias -it will take more time to see full effect in CHF pts -not used as much as in the past b/c of amiodarone |
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CHF
Effects on WARFARIN |
-at the onset of acute heart failure:
*increase in INR *hepatic congestion will increase *Give an extra dose of furosemide will help bring down INR -Chronic heart failure *usually no problems w/ elevated INR |
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Intro to Aminoglycosides (AG)
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-AG are most widely used antibiotics for GRAM NEGATIVE infections in both hospital & outpt
-have CONCENTRATION-DEPENDENT adverse effects (monitor trough levels to dec chance of nephro & ototoxicity) -Gentamicin & Tobramycin (similar dosing & susceptibilities) -Amikacin (is different in regards to dosing & calculations b/c requires higher dosing & has better resistance to Pseudomonas) - |
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Aminoglycosides
MONITORING |
-improved efficacy & reduced toxicity by monitoring AG conc & basing dosing adjustments upon these results
-concentration-effect & concentration-toxicity relationship -wide intrapatient variation in plasma concentrations & pharmacokinetic parameters occur w/out concurrent change in renal function -wide interpatient variation w/ same dose of drug -AG assays have made monitoring plasma concentrations practical in clinical setting |
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Aminoglycosides
ABSORPTION |
-given IV or IM
-NOT PO b/c of lack of absorption from GI -IM injection - well absorbed -pts w/ CHF or gram - sepsis can have perfusion at injection site & cause hypotension (sepsis) or decreased CO (CHF) -peak concentration obtained after IM injection usually occurs w/in 30-90 mins after injection -IV INFUSIONS are usually 30-60 mins in duration & are safer than IV BOLUS due to dec peak conc & therefore dec incidence of peak-associated toxicity |
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Aminoglycosides
DISTRIBUTION |
-distributes WELL into body fluids (peritoneal, synovial & pleural fluids)
-distributes POORLY into bile, feces, prostatic, amniotic fluid & also CNS -protein binding (<10% not clinically significant) -distributes into pharmacological space similar to extracellular fluid compartment (normal 20-25% of body weight) -HIGH Vd = pts w/ CHF, immediately postpartum, dec renal function will have a change in distribution due to dx state changes in extracellular water compartment. -LOW Vd = dehydration -14-66% of serum AG concentrations found in bronchial secretions -Ascities (peak conc rise slowly, achieving peak levels 2-6 hrs after a dose, therefore, 2-4 hrs after a dose, the serum & ascites concentrations are comparable). -AG concentrate in the renal cortical tissue 10-50 times the serum concentration -Changes in the extracellular fluid will have a DIRECT effect on the changes in the AG disposition -range in Vd = 0.15-0.35 L/kg |
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Aminoglycosides
METABOLISM |
clinically insignificant
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Aminoglycosides
EXCRETION |
-majority eliminated renally primarily by glomerular filtration (95-98%)
-normal elimination t1/2 *gent/tobra = 2.5-4 hrs *amikacin = 0.8-2.1hrs -total body clearance demonstrates considerable pt to pt variability (8.4 - 24.2 ml/kg/hr in pts w/ normal CrCl) |
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Aminoglycosides
THERAPEUTIC RANGE |
-Correlation between efficacy & peak concentrations
-no evidence of efficacy & trough concentration -most clinicians use therapeutic range of 5-10 mcg/ml (mg/L) as therapeutic. |
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Aminoglycosides
THERAPEUTIC RANGE Peak conc desired for tobra/gent in the following UTI Pyelonephritis Cellulitis Intra-abdominal infection Pneumonia Bacteremia Septic shock, neutropenia Abscess Gram + organism (for synergy only; ie S.epidermidis, S.aureus) |
UTI = ~4-5 mg/L
Pyelonephritis = ~5-6.5 mg/L Cellulitis = >5 mg/L (depends on organism & site) Intra-abdominal infection = ~6-8 mg/L (depends on org) Pneumonia = 7-8.5 mg/L (depends on org & if it is nosocomial (harder to treat) Bacteremia = >7-8.5 mg/L Septic shock, neutropenia = >7-8.5mg/L Abscess = 6-9 mg/L Gram + organism (for synergy only; ie S.epidermidis, S.aureus) = 3.5-4.5 mg/L |
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Aminoglycosideds
THERAPEUTIC RANGE Peak conc desired for tobra/gent in the following UTI Pyelonephritis Cellulitis Intra-abdominal infection Pneumonia Bacteremia Septic shock, neutropenia Abscess Gram + organism (for synergy only; ie S.epidermidis, S.aureus) |
UTI = 15-20mg/L
Pyelonephritis = 15-20mg/L Cellulitis = 15-20mg/L Intra-abdominal infection = 20-25 mg/L Pneumonia = 25-30mg/L Bacteremia = 25-30mg/L Septic shock, neutropenia = 25-30mg/L Abscess = 20-30mg/L Gram + organism (for synergy only; ie S.epidermidis, S.aureus) = 10-15 mg/L |
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Aminoglycosideds
TOXICITY |
-high trough concentrations assoicated w/ nephrotoxicity & ototoxicity
-gent/tobra = >2.0 mcg/ml *for empiric dosing, want to shoot for levels <1mg/L -amikacin/kanamycin = >10 mcg/ml *for empiric dosing, want to shoot for levels <8mg/L |
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Aminoglycosideds
NEPHROTOXICITY RISK FACTORS |
-age (younger & older)
-AG use in previous 4 wks -trough concentration >2 mg/L -total daily dose -cumulative dose >14 days (these next ones are the ones different from ototoxicity) -Renal insufficiency -existing hypovolemia &/or shock -concurrent use of nephrotoxic drugs including vancomycin or amphotericin B -liver dx |
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Aminoglycosideds
OTOTOXICITY RISK FACTORS |
-age (young and elderly)
-AG in previous 4 wks -trough concentration >2 mg/L -total daily dose -cumulative dose >14 days (these next ones are the different from nephrotoxicity) -hemodialysis -concurrent ototoxic drugs including loop diuretics, vancomycin -prior AG exposure |
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Aminoglycosides
MOA of nephrotoxicity |
AG molecule is brought to the proximal tubule for excretion. At periods of high conc the AG molecule is absorbed into the brush border cell of the proximal tubule. A vacuole forms around the AG molecule by the process of pinocytosis. The vacuole ruptures & AG molecule then interferes w/ oxidative phosphorylation & ATP synthesis. The result then is the cell dies & is secreted into the urine. Casts in the urine can be an early indicator of proximal tubule damage. Typical findings are dec GFR, inc SCr, inc BUN, impaired urinary concentrating ability -- all which lead to non-oliguric renal failure. Incidence is 6-10% in comparative trials.
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Aminoglycosides
MOA of ototoxicity |
8th cranial nerve damage includes auditory, vestibular dysfunction up to 4-6 wks after tx has ended. Symptoms of early cochlear damage include sensation of fullness & tinnitus. AG alters Na-K pump thereby causing a change in electrical potential & intracellular osmotic pressure. Early changes affect outer hair cells of the organ of Corti - affecting high frequency 4,000-8,000 Hz. Vestibular dysfunction follows cochlear damage manifested by vertigo, N, dizziness, & nystagmus. Vestibular damage is permanent. Incidence is 2-10% of pts treated.
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Aminoglycosides
MOA of neuromuscular blockade |
AG molecule interferes w/ Ca & immediate release of ACh at presynaptic membrane level. Caution w/ concurrent use of NMB agents & in pts w/ Myasthenia Gravis
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Aminoglycosides
DOSING |
-Recommended dosage
*gent/tobra = 1mg/kg/dose for peaks 3-4.5 mg/L 2mg/kg/dose for peaks 6-8 mg/L *Amikacin 5-7.5 mg/kg/dose -Monitoring *Steady state *Peak level: 30 mins after end of infusion *trough level 30 mins before start of infusion *infuse over 30mins for standard dosing, over 1 hr for high dose QD AG *monitor levels q 5-7 days or if there is a change in renal function |
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Aminoglycosides
PEDIATRICS & NEONATES Vd & Crcl |
Pediatrics
* <5 yo = Vd = 0.5L/kg * >5 yo = Vd = 0.25L/kg *CrCl = [(0.55)(ht in cm)]/ Scr Neonate *t1/2 = 4-12 Hrs *CrCl = [(0.45)(ht in cm)]/Scr |
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Aminoglycosides
Estimating Vd |
-Normal 0.22-0.25 L/kg
-Low 0.15-0.21 L/kg Dehydration Output>Input -High 0.26-0.35 L/kg (will use 0.27-0.28 if pt is in ER/ICU) ICU Neutropenia Edema/CHF Low Albumin (malnutrition) Input>Output Ascites Ventilator Pregnant/immediately postpartum (Vd decreases to normal 4-5 days after delivery) |
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Aminoglycosides
Obese pts |
-obese pts are 20% or greater over the IBW.
-Dosing weight = IBW + 0.4 (ABW-IBW) -use dosing weight to calculate DOSE & VOLUME OF DISTRIBUTION. -Otherwise use the actual body weight if pt is of normal weight |
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Aminoglycosides
estimating Kel (elimination rate constant) |
kel = (0.00285 x CrCl) + 0.015
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Aminoglycosides
determining the dosing interval |
Tau = t1/2 x 3
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Aminoglycosides
determining CrCl |
using the cockcroft-gault equation:
[(140-age) * IBW (kg)] / (72 * SCr) --multiply by 0.85 if pt is FEMALE -Use IBW or ABW = whatever is lower of the two -If SCr is < 1, use 1 mg/dl if pt is older than 60 yo. |
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Aminoglycosides
Steady state/ checking if pt is at steady state |
To check if a pt is at steady state, multiply t1/2 by 5, and if the duration of therapy is greater than the result of this equation, the pt is at steady state.
When a pt is at steady state, you can use the Vd equation to solve for Vd. |
