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Nephrotoxicity/neurotoxicity
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Polymyxins
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Hot flashes
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Tamoxifen, clomiphene
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Coronary vasospasm
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Cocaine, sumatriptan
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Acute cholestatic hepatitis
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Macrolides
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Dilated cardiomyopathy
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Doxorubicin (Adriamycin), daunorubicin
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Serotonin syndrome?
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excitation, hyperpyrexia, hypertension, profuse sweating, and rigidity.26 This may progress to seizures, coma, and death
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SLE-like syndrome
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Hydralazine, INH, Procainamide, Phenytoin
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Garlic
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Possible antiplatelet effects, caution with warfarin, aspirin, ibuprofen.
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Cutaneous flushing
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Niacin, Ca2+ channel blockers, adenosine, vancomycin
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Smoking
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Smoking increases the activity of drug-metabolizing liver enzymes
This can decrease effects of diazepam, theophylline, chlorpromazine, and amitriptyline
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Ephedrine
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Potentiates caffeine effects on heart rate and BP.
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Erythromycin
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Accumulation in presence of CYP3A inhib. such as verapamil & diltiazem so inc. risk sudden cardiac death from prolonged QT
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Hemolysis in G6PD-deficient patients
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Isoniazid (INH), Sulfonamides, Primaquine, Aspirin, Ibuprofen, Nitrofurantoin
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Propranolol
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Dec. hepatic blood flow and reduces hepatic clearance of lidocaine.
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Focal to massive hepatic necrosis
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Halothane, valproic acid, acetaminophen, Amanita phalloides
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Diseases and Conditions
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Impaired renal and hepatic function are the most important conditions that can alter drug activity
Renal and hepatic diseases influence patient responses to certain drugs
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10% of caucasians are
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CYP2D6 poor metabolizers (homozygous for mutant alleles) & have a 10-fold reduced metabolic efficiency. They can have 10-fold higher steady-state drug levels. CYP2D6 metabolizes beta blockers & antiarrhythmics.
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inhibitors of hepatic metabolism
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INHIBITORS
Cimetidine
Ketoconazole
Erythromycin
Disulfiram
Ritonavir
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Squill, strophanthus, & oleander - contain cardiac glycosides
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Potentiates digoxin toxicity.
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Drug:Warfarin (Coumadin ®), Properties Promoting Drug Interaction:
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* Metabolized by CYP2C9 isozyme (which can be induced or inhibited by other drugs) * Binding to plasma proteins (can be reduced by other drugs) * Action to inhibit synthesis of Vit K dependent clotting factors (can be antagonized or increased by other drugs & conditions) * Vit K producing bacteria in the gut can be eliminated by antibiotics * Anticoagulant effects can be altered with other drugs
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Drug Interactions:Drug: Cyclosporin
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* Barbiturates: induce CYP & increase cyclosporin metabolism * Rifampin, St. John's wort: induce CYP & increase cyclosporin metabolism * Macrolide antibiotics: compete for CYP, decrease cyclosporin metabolism
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pharmacokinetic interaction def
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occurs when one drug alters the absorption, distribution, metabolism, or elimination of another.
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Ginseng
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Inhib. CYP 3A4, inc. Cp & effects of nifedipine
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Drug: CyclosporinProperties Promoting Drug Interaction:
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* Susceptible to inhibition of its metabolism by CYP3A4 inhibitors * Metabolism is inducible
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MAOi + which drugs can cause serotoninergic syndrome?
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SSRIs / meperidine
dextromethorphan,28 and the analgesics, propoxyphene, and tramadol. Other than some poorly documented case reports, the evidence suggests that morphine and fentanyl do not produce this interaction.
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St. John's Wort
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Induces CYP 3A4, 1A2, 2C9 and inc. metab / dec. effects of cyclosporin, warfarin, norethindrone, and ethinyl estradiol. Induces p-glycoprotein transporter inc. digoxin exretion in G.I. tract.
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tetracycline is inactivated by?
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by chelation if it is given together with antacids containing polyvalent cations such as Mg2+, Ca2+, or Al3+.
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Drugs that may decrease warfarin effect:
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* Vitamin K: increased synthesis of clotting factors * Chlorthalidone & Spironolactone: increased synthesis of clotting factors * Hypothyroidism: decreased turnover of clotting factors.
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weak acids get trapped in
weak bases get trapped in>>.
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more basic environment
more acidic environment
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Hepatitis
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INH
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Seizures
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Bupropion, imipenem/cilastatin
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Diabetes insipidus
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Lithium, demeclocycline
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Photosensitivity
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Sulfonamides, Amiodarone, Tetracycline
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Pulmonary fibrosis
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Bleomycin, busulfan, amiodarone
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Aplastic anemia
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Chloramphenicol, benzene, NSAIDs, propylthiouracil, methimazole
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Hemorrhagic cystitis
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Cyclophosphamide, ifosfamide (prevent by coadministrating with mesna)
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Protamine
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Binds to adn inactivates heparin.
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Cough
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ACE inhibitors (note: ARBs like losartan--no ???)
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Drug Interactions: Statins
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* Clarithromycin, Cyclosporin, Erythromycin: decreased statin metabolism due to competitive inhibition of CYP 3A4, elevated statin levels
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Ginko biloba
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Antagonist of platelet activating factor. Inc. risk bleeding with warfarin, ibuprofen, aspirin; inhib CYP3A4 and inc. Cp & effects of nifedipine.
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Estrogen
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Inhib. CYP1A2 and CYP2C19 affecting many drugs.
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Potentiation
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one drug prolongs the effects of another drug
Is often desirable in order to build up a sufficient drug level or to prolong its effect
Ex. toxicity caused when cimetidine is combined with asthma medications containing theophylline
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Epinephrine
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Dec. blood flow and thereby absorption of lidocaine.
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Antagonism
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when two drugs decrease the effects of each other
Ex. When ibuprofen and aspirin are taken together; they stop each other’s action
Tetracycline and antacids should not be used together, tetracycline must be absorbed in the stomach and antacids inhibit absorption
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Patient Variables Affecting Drug Interaction
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Age
Genetic factors
Diseases and conditions
Diet
Alcohol consumption
Smoking
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Drug Interactions: Quinidine
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BASICALLY DRUGS THAT ALKALINIZE THE URINE, CIMETIDINE, DIGOXIN, DRUGS THAT PROLONG THE QT INTERVAL, RIFAMPIN. * Drugs that alkalinize the urine (Acetazolamide, Na bicarbonate, Carbonic Anhydrase Inhibitors): decreases renal excretion & elevate plasma quinidine levels. * Cimetidine: cimetidine is a potent inhibitor of all clinically relevant CYP isozymes and p-glycoprotein. Avoid use with amiodarone, digoxin & warfarin. * Digoxin: quinidine displaces digoxin from tissue binding sites & inhibits p-glycoprotein mediated renal excretion * Drugs that prolong the QTc interval: additive effects to prolong the QTc and cause cardiac arrhythmias (torsade de pointes) * Rifampin: (increases hepatic metabolism of quinidine)
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inducers of hepatic metabolism
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INDUCERS I
Phenobarbital
Phenytoin
Rifampicin
Carbamazepine
Ethanol
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Drug Interaction
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An interference of a drug with the effect of another drug, nutrient, or laboratory test.
Usually the result of taking more than one drug concurrently
can occur during liberation, absorption, distribution, biotransformation, or excretion
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Drug: RifampinDrug Interactions:
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It will acclerate the metabolism of other drugs that are metabolized by CYP. The list is very long, but include oral contraceptives, anticonvulsants, theophylline, sulfonylurea hypoglycemic drugs, corticosteroids, etc.
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Amiodarone (Cordarone ®) drug interactions
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Basically DIGOXIN, WARFARIN, AND CIMETIDINE * Digoxin: amiodarone inhibits renal digoxin excretion via p-glycoprotein. Coadministration will increase digoxin plasma levels. * Warfarin: amiodarone inhibits the CYP2C9 mediated metabolism of S-warfarin, resulting in increased warfarin plasma levels. * Cimetidine: cimetidine is a potent inhibitor of all clinically relevant CYP isozymes and p-glycoprotein. Avoid use with amiodarone & warfarin.
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lidocaine concentration incrases w/
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decreased hepatic blood flow, pressor administration
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Passionflower, juniper, verbena
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Vit. K content can dec. warfarin effect.
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Drug: Quinidine (generic)Properties Promoting Drug Interaction:
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* Metabolism is inducible * Quinidine is a potent inhibitor of CYP2D6. It will conver a rapid metabolizer to a slow metabolizer phenotype. This is the same isozyme inhibited by fluoxetine, etc. * Renal excretion is susceptible to changes in urine pH * Renal excretion occurs via p-glycoprotein & can antagonize elimination of other drugs * additive effects with other agents that prolong the QTc interval
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rate limiting factor for elimination in drugs w/ low extraction ratio?
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enzyme activity ; diazepam, lorazepam
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Senna and cascara - lead to K+ loss
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Potentiates digoxin toxicity.
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monamide oxidase, distribution of the enzyme,
function
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is distributed throughout the body, with the largest amounts found in the liver, kidney, and brain. MAO is located on the outer surface of mitochondria in the presynaptic terminals of noradrenergic, dopaminergic, and serotonergic neurons in the CNS and periphery. It acts to regulate the presynaptic pool of norepinephrine, dopamine, epinephrine, and serotonin available for synaptic transmission
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Drugs that may decrease digoxin effect:
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RIFAMPIN & ST. JOHN'S WORTRifampin (# is the strongest inducer of both cyt P450 & p-glycoprotein & will reduce plasma digoxin levels primarily by inducing intestinal p-glycoprotein. P-glycoprotein acts to reduce drug absorption in the GI tract by pumping drug back into the GI lumen.)# St. John's wort: (St. John's wort is a potent p-glycoprotein inducer that will increase digoxin's renal clearance & reduce intestinal absorption of digoxin. Induction may take 2-4 weeks to develop & may persist for 2-4 weeks after the inducer is stopped.)
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Danger of using NO w/ oxygen for pulmonary hypertension in the newborn?
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formation of Nitrous dioxide, quite toxic, and concentrations >10 ppm can produce pulmonary edema and alveolar hemorrhage. The problem is circumvented by allowing oxygen and NO to mix in the breathing circuit just before administration
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