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269 Cards in this Set
- Front
- Back
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What are the symptoms of CO poisoning?
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Hypoxia to brain (headache, confusion, convulsions, respiratory failure, coma)
Hypoxia to heart (chest pain, syncope) Cyanosis |
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What is the mechanism of CO poisoning?
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CO binds to hemoglobin with dose-dependent levels of carboxyhemoglobin.
Carboxyhemoglobin prevents O2 binding to Hb and prevents O2 dissociation. |
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What is the antidote or therapy for CO poisoning?
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100% O2
Hyperbaric oxygen for serious cases or pregnant women |
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What are the symptoms of CN poisoning?
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Hypoxia without cyanosis
Bitter almond smell Coma Metabolic acidosis |
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What is the mechanism of CN poisoning?
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Cyanide binds to and inhibits cytochrome oxidase, stopping electron transport. Death occurs to respiratory failure.
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What therapeutic drug can cause CN poisoning? What is used to treat it?
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Nitroprusside releases CN. Thiosulfate is is used to treat it.
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What is the antidote or therapy for CN poisoning?
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1. Amyl nitrite (Hb-->MetHb, traps CN)
2. Sodium thiosulfate (CN-->thiocyanate, renal secretion) 3. Methylene blue (MetHb-->Hb) |
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What are the symptoms of MeOH poisoning?
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"Feeling of being in a snowfield"
Blurred vision Papilledema Abdominal pain Common in alcoholics |
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What is the mechanism of MeOH poisoning?
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Alcohol dehydrogenase: MeOH --> formaldehyde
Aldehyde dehydrogenase: formaldehyde --> formic acid Formic acid causes retinal damage, blindness, profound metabolic acidosis |
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What is the antidote or therapy for MeOH poisoning?
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Ethanol saturates alcohol dehydrogenase
Hemodialysis removes formic acid and methanol Bicarbonate corrects acidosis |
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What are the symptoms of Pb poisoning?
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Hypochromic microcytic anemia
Basophilic stippling Lead lines Encephalopathy (seizures in children) Peripheral neuropathy (adults) Kidney damage (adults) Abdominal pain |
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What is the mechanism of Pb poisoning?
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Pb accumulates in bone (T1/2>20y).
Pb decreases RBC life-span and synthesis Pb inhibits d-aminolevulinic acid (ALA) dehydratase, increasing ALA levels Lead inhibits ferrochetalase, increasing protoporphyrin IX levels |
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What is the antidote or therapy for Pb poisoning?
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1.Calcium disodium EDTA removes lead from bone (not cell permeable)
2. Dimercaprol removes lead from cells (adults, children with CNS involvement) 3. Succimer removes lead from cells (children) 4. Penicillamine removes mild lead toxicity and other metals |
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What are the symptoms of Fe poisoning?
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Acidosis
Liver failure GI irritation and bleeding Occurs in children who eat iron pills |
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What is the mechanism of Fe poisoning?
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Iron induces lipid peroxidation in mitochondria, inhibiting electron transport.
Compensatory glycolysis generates lactic acid causing metabolic acidosis. |
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What is the antidote or therapy for Fe poisoning? When is it used?
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Deferoxamine removes iron from ferritin and is used if iron levels exceed 400ug/dL
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What are the symptoms of chlorinated aromatic hydrocarbon poisoning? What is an example of a chlorinated aromatic hydrocarbon-containing substance?
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Agent Orange contaminated by Dioxin
Chloracne Porphyria Liver damage CNS dysfunction Impaired reproduction |
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What is the mechanism of chlorinated aromatic hydrocarbon poisoning?
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Chlorinated aromatic hydrocarbons bind to AhR, inducing transcription of Ah hydroxylase and ALA synthase.
Chlorinated aromatic hydrocarbons also mimic estrogens. |
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What is the antidote or therapy for chlorinated aromatic hydrocarbon poisoning?
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Cholestyramine removes bile acid needed for enterohepatic reciculation.
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What are the symptoms of paraquat poisoning? What is an example of a paraquat-containing substance?
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Herbicides contain Paraquat
Dyspnea Nonproductive cough Hypoxia Bilateral infiltrates on CXR Inflammation and fibrosis |
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What is the mechanism of paraquat poisoning?
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Paraquat undergoes redox cycle, creating toxic oxygen radicals causing lipid peroxidation, cell death, inflammation, and fibrosis.
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What is the antidote or therapy for paraquat poisoning?
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100% O2 therapy is contraindicated
Serial activated charcoal removes toxins from enterohepatic circulation Hemoperfusion removes plasma protein-bound paraquat Antioxidants (Vitamins E, C) minimize damage |
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What are the symptoms of warfarin/superwarfarin poisoning?
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GI bleeding and melena
Hematuria Epistaxis Multiple ecchymotic lesions Increase in prothrombin time Decrease in hemoglobin |
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What is the mechanism of warfarin/superwarfarin poisoning?
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Warfarin blockvVitamin K1 epoxide reductase, decreasing gamma-carboxylation of clotting factors, causing to an anticoagulative effect with a low therapeutic index
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What is the antidote or therapy for warfarin/superwarfarin poisoning?
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Vitamin K1 for a few days (warfarin poisoning)
Vitamin K1 for months (superwarfarin poisoning) IV fresh frozen plasma or factor IX for severe cases |
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What is a substrate for CYP3A4?
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Cyclosporin A
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What is an inhibitor of CYP3A4?
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Erythromycin
Ketoconazole, Itraconazole, Fluconazole Metronidazole Grapefruit juice |
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What is an inducer of CYP3A4?
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Rifampin
St. John's Wort |
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Describe CYP3A4's drug specificity
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50% of all CYP-mediated drug oxidations
Large active site Present in liver and intestinal mucosa Responsible for first-pass metabolism |
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Describe CYP2D6's drug specificity
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30% of all CYP-mediated drug oxidations
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Describe CYP2C9's drug specificity
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10% of all CYP-mediated drug oxidations
Prefers weakly acidic drugs |
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What is a substrate of CYP2C9?
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Warfarin
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What is an inducer of CYP2C9?
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Rifampin
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Describe CYP1A's drug specificity
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Arylhydrocarbon hydroxylase
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What is an inhibitor of CYP1A?
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Fluoroquinolones
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Describe CYP2E1's drug specificity
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2% or less of CYP-mediated drug oxidation
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What is an inducer of CYP2E1?
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Isoniazid
Chonic alcohol |
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Chronic alcohol induces which CYP450 isoenzyme?
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CYP2E1
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Glucuronidation is low in what age group? What is a possible outcome?
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Neonates and infants; can lead to bilirubin-induced encephalopathy (kernicterus) or chloramphenicol-induced gray baby syndrome
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Oxidative reactions are low in what age group?
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Children
Elderly |
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Drugs for the elderly should be metabolized by what phase reactions? What is one example?
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Phase II: conjugation
Elderly should be given lorazepam rather than diazepam |
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Drug clearance is high in what age group?
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Children
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Creatinine clearance reflects what physiological function?
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Kidney function; creatinine clearance reflects the GFR.
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Object drugs have a narrow or wide therapeutic index?
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Narrow
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Phase I drug metabolism includes what reactions?
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Oxidative reactions mediated by CYP450
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Phase II drug metabolism includes what reactions? Where does each occur?
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Glucuronidation (microsome)
Sulfation (cytoplasm) Acetylation (cytoplasm) |
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What is a substrate of CYP2E1?
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Acetaminophen
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What is a substrate of CYP1A?
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Polyaromatic Hydrocabons
Caffeine Theophylline |
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What is the signalling pathway of PGD2? What are its effects on the:
Cardiovascular system Blood Renal system GI tract Respiratory system Uterine smooth muscle Central nervous system |
PGD2 induces adenylate cyclase which increases cAMP
CV: Blood: Renal: GI: Resp: Uterus: CNS: Induces natural sleep |
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What is the signalling pathway of PGI2?
What are its effects on the: Cardiovascular system Blood Renal system GI tract Respiratory system Uterine smooth muscle Central nervous system |
PGI2 induces adenylate cyclase which increases cAMP
CV: Vasodilation Blood: Anti-coagulation Renal: Increased renin, decreased pee GI: Increased mucus, decreased acid Resp: Bronchodilation Uterus: Relax CNS: Pain |
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What is the signalling pathway of PGE?
What are its effects on the: Cardiovascular system Blood Renal system GI tract Respiratory system Uterine smooth muscle Central nervous system |
PGE2 induces or inhibits AC which increases or decreases cAMP
CV: Vasodilation Blood: Anti-coagulation Renal: Decreased ADH, increased pee GI: Decreased acid Resp: Bronchodilation Uterus: Contract CNS: Fever, Pain |
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What is the signalling pathway of PGF2a? What are its effects on the:
Cardiovascular system Blood Renal system GI tract Respiratory system Uterine smooth muscle Central nervous system |
PGF2a induces PLC which increases DAG and IP3 which increases Ca2+
CV: Vasoconstriction Blood: Renal: GI: Peristalsis, diarrhea Resp: Bronchoconstriction Uterus: Contract CNS: |
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What is the signalling pathway of TXA2? What are its effects on the:
Cardiovascular system Blood Renal system GI tract Respiratory system Uterine smooth muscle Central nervous system |
TXA2 induces PLC which increases DAG and IP3 which increases Ca2+
CV: Vasoconstriction Blood: Coagulation Renal: GI: Resp: Bronchoconstriction Uterus: Contract CNS: |
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What is the signalling pathway of LT? What are its effects on the:
Cardiovascular system Blood Renal system GI tract Respiratory system Uterine smooth muscle Central nervous system |
LT induces PLC which increases DAG and IP3 which increases Ca2+
CV: Endothelial contraction, exudation, decreased blood volume Blood: Chemotaxis, activation Renal: GI: Peristalsis Resp: bronchoconstriction, bronchial edema Uterus: CNS: Pain |
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What is the mechanism of action of Dexamethasone?
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Dexamethasone stimulates synthesis of lipocortin which inhibits PLA2
Dexamethasone directly suppresses COX-2 expression |
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Which drug stimulates synthesis of lipocortin? What is the effect?
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Dexamethasone stimulates synthesis of lipocortin, which inhibits PLA2 and directly suppressses COX-2 expression.
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What is the mechanism of action of aspirin? What are its effects?
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Non-selective COX-1/2 inhibition by irreversible acetylation
-Anti-inflammatory -Anti-pyretic -Analgesic -Anti-platelet aggregation |
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Which drug non-selectively irreversibly acetylates COX-1/2? What are its effects?
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Aspirin
-Anti-inflammatory -Anti-pyretic -Analgesic -Anti-platelet aggregation |
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What is the mechanism of action of acetaminophen? What are its effects?
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Weak non-selective inhibition of COX-1/2, strong inhibition of COX-3
-Anti-pyretic -Analgesic |
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Which drug weakly non-selectively inhibits COX-1/2 and strongly inhibits COX-3? What are its effects?
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Acetaminophen
-Anti-pyretic -Analgesic |
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What is the mechanism of action of Indomethacin, Ibuprofen, and Naproxen? What are their effects?
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Non-selective inhibition of COX-1/2
-Anti-inflammatory -Anti-pyretic -Analgesic -Anti-platelet aggregation |
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Which drugs non-selectively inhibit COX-1/2? What are their effects?
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Indomethacin
Ibuprofen Naproxen -Anti-inflammatory -Anti-pyretic -Analgesic -Anti-platelet aggregation |
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What is the mechanism of action of Celecoxib and Rofecoxib? What are their effects?
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Selective COX-2 inhibition
-Anti-inflammatory -Anti-pyretic -Analgesic |
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Which drugs selectively inhibit COX-2? What are their effects?
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Celecoxib
Rofecoxib -Anti-inflammatory -Anti-pyretic -Analgesic |
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Where is cardiovascular COX-2 located? What does it synthesize? What is the effect?
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COX-2 is located in the vascular endothelium and synthesizes PGI2, resulting in anti-platelet aggregation.
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Where is PGI2 synthesized in the cardiovascular system? Which COX isoenzyme is inolved? What is the effect?
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PGI2 is synthesized by COX-2 in the vascular endothelium resulting in anti-platelet aggregation.
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Where is cardiovascular COX-1 located? What does it synthesize? What is the effect?
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COX-1 is located in the platelets and synthesizes TXA2, resulting in platelet aggregation.
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Where is TXA2 synthesized in the cardiovascular system? Which COX isoenzyme is involved? What is the effect?
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TXA2 is synthesized by COX-1 in platelets resulting in platelet aggregation.
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What is the mechanism of action of Zileuton? What is its effects?
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Zileuton inhibits lipoxygenase, preventing leukotriene synthesis, which are potent mediators of allergic reactions and asthma, producing bronchodilation.
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Which drug inhibits lipoxygenase? What is its effects?
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Zileuton inhibits lipoxygenase, preventing leukotriene synthesis, which are potent mediators of allergic reactions and asthma, producing bronchodilation.
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What is the mechanism of action of Zafirlucast and Montelucast? What are their effects?
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Zafirlucast and Montelucast block leukotriene receptors, which are potent mediators of allergic reactions and asthma, producing bronchodilation.
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What is the mechanism of action of Alprostadil? What are its effects?
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PGE1 agonism
Maintains the patency of the ductus arteriosus |
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What is the mechanism of action of Misoprostol? What are its effects?
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PGE1 agonism
Misoprostol prevents gastric ulcers associated with non-selective COX-1/2 inhibitors. |
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What is the mechanism of action of Dinoprostone? What are its effects?
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PGE2 agonism
Dinoprostone promotes uterine contractions, facilitating labor or inducing abortion. |
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What is the mechanism of action of Latanoprost? What are its effects?
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PGF2a agonism
Latanoprost reduces intraocular pressure by increasing aqueous humor outflow for the treatment of glaucoma. |
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What is the mechanism of action of Epoprostenol and Treprostinil? What is their clinical use?
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PGI2 agonism
Epoprostenol lowers vascular pressure and is useful in treating pulmonary hypertension. |
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What is the signalling pathway of PAF? What are its effects on:
CV: Blood: Renal: GI: Resp: Uterus: CNS: |
PAF activates GPCR which activates PLC, PLD, PLA2, causing:
CV: vasodilation, endothelial contraction Blood: Increased aggregation Renal: GI: Ulcerogenesis, Peristalsis Resp: Bronchospasm, bronchoconstrictoin Uterus: Contraction CNS: pain |
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What is the mechanism of action of ginkgolide B? What are its effects?
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PAF antagonism
Interference with ovulation, implantation, and parturition |
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How is histamine synthesized?
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Histidine is converted to histamine (l-histidine-decarboxylase)
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How is histamine metabolized?
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Histamine is converted to inactive metabolites (1.histamine-N-methyl transferase 2.MAO-B)
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What are the main storage cells of histamine? Where are they located? Where is it also found?
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Mast cells residing in skin, mucosa of bronchial tree, and intestinal mucosa.
Histamine is also found in the CNS and in basophils in the blood. |
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How is histamine released? What other factors are also released? What is the effect?
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IgE on FcE-receptors of mast cells and basophils bind antigen, activating PLC and causing release of histamine, ATP, PAF, PGD2, LTD4, and kinins.
These all result in an allergic reaction characterized by bronchoconstriction, hypotension, increased capillary permeability, and edema. |
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What is the mechanism of action of beta-adrenoreceptor agonists? What are their primary and secondary effects?
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Beta-adrenoreceptor agonists primarily cause bronchial relaxation (physiological antagonism of histamine) and secondarily increase cAMP and inhibit the secretion of histamine.
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What is the mechanism of cromolyn sodium and nedocromil? What is their effects? Who is nedocromil indicated for?
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Cromolyn sodium and nedocromil inhibits release of mast cell mediators in the lung.
Nedocromil is used only in asthma patients. |
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Which compounds cause histamine-related reactions?
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Organic bases, tubocurarine, succinylcholine, morphine (not fentanyl), vancomycin, and mastoparin (wasp venom).
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Histamine receptors are members of what receptor superfamily?
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G-protein coupled receptor superfamily with 7 membrane-spanning domains.
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What are the effects of H1 receptors?
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NO release --> vasodilation
Endothelial cell contraction --> transudation Smooth muscle contraction: -Bronchoconstriction -Peristalsis -Uterus Pain and itching |
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What are the effects of H2 receptors? What is the signalling transduction pathway?
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Increased AC --> Increased cAMP
CV: Vasodilation, Increased HR GI: Gastric Acid secretion |
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What are the effects of H3 receptors?
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Feedback inhibition of histamine, norepinephrine, serotonin, and acetylcholine release
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Which antihistamines are 1st generation H1 receptor antagonists?
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Diphenhydramine
Pyrilamine Chlorpheniramine Promethazine Cyproheptadine |
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Which antihistamines are 2nd generation H1 receptor antagonists?
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Certirizine
Loratadine Fexofenadine |
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Why don't 2nd generation antihistamines show sedating effects?
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They are less lipid soluble and do not penetrate the CNS.
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Which antihistamines are H2 receptor antagonists? What are their effects? Which is worse than the others? Which has more bioavailability? Which are excreted by the kidneys?
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Cimetidine (worse side effects especially for elderly, excreted by kidneys)
Ranitidine (excreted by kidneys) Famotidine Nizantidine (90% bioavailability) Reduce acid secretion. |
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How is serotonin synthesized?
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Tryptophan is converted to 5-Hydroxytryptophan (Tryptophan Hydroxylase, Aromatic L-Amino Acid Decarboxylase)
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Where is serotonin produced and stored?
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Produced in enterochromaffin cells
Stored in platelets |
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How is serotonin metabolized? How is this inhibited?
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5-HT is converted to inactive metabolites (MAO-A, aldehyde dehydrogenase). Clorgyline inhibits MAO-A.
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What are the substrates of MAO-A and MOA-B, respectively? What are inhibitors of each?
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MAO-A: 5-HT, NE (clorgyline)
MAO-B: Histamine, beta-phenylethylamine (selegiline) |
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What is the mechanism of action of clorgyline? What is its effect?
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Clorgyline inhibits MAO-A, decreasing metabolism of 5-HT and NE.
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What is the mechanism of action of selegiline? What is its effect?
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Selegiline inhibits MAO-B, decreasing metabolism of Histamine and b-Phenylethylamine.
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What is serotonine's effect on the cardiovascular system? Which receptors mediate this? What can chronic high levels of 5-HT lead to?
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Vasoconstriction: 5-HT1b,5-HT2a
EDRF release: 5-HT2b Vasodilation: 5-HT7 Chronic high levels of 5-HT can lead to subendocardial fibroplasia. |
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What is serotonin's effect on vascular smooth muscle? What receptors mediate this?
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Direct constriction: 5-HT1b 5-HT2a
Indirect relaxation (EDRF): 5-HT2b 5-HT7 |
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What is serotonin's effect on bronchial smooth muscle? What receptors mediate this?
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Bronchial smooth muscle contraction: 5-HT2a 5-HT2c
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What is serotonin's effect on the GI tract? How is it mediated?
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Motility: Many
Emesis: 5-HT3 |
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What is the mechanism of action of fenfluramine? What is its effect?
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Fenfluramine is a halogenated amphetamine which indces 5-HT release.
Fenfluramine is used for appetite suppression. |
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What is the mechanism of action of Fluoxetine? What is its effect?
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Fluoxetine inhibits 5-HT reuptake and is used for treatment of endogenous depression and OCD.
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What is the clinical use of Sumatriptan?
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Sumatriptan is used to treat acute migraines
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What is the mechanism of action of Tegaserod? What is its effect?
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Tegaserod is a 5-HT4 agonist used to stimulate peristalsis and gastric emptying to treat IBS with constipation.
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What is the mechanism of action of Ondansetron? What is its effect?
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Ondansetron is a 5-HT3 antagonist used to treat chemotherapy-induced nausea and emesis.
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What is methysergide used for?
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Migraine prophylaxis
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What is the mechanism of action of Cyproheptadine? What is its effect?
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Cyproheptadine is a 5-HT2a antagonist used in the treatment of postgastrectomy dumping syndrome.
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How do kinins cause edema?
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Arteriolar vasodilation
Venous constriction Contraction of endothelial cells |
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What is the mechanism of action of Captopril and Enalapril? What is their effect? What are their side effects?
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Captopril and Enalapril are ACE inhibitors which decrease conversion of angiotensin I into angiotensin II and decrease metabolism of kinins.
ACE inhibitors lower blood pressure for the treatment of htn and CHF. Side effects include coughing. |
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What is the mechanism of action of Losartan and Valsartan?
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Losartan and Valsartan are angiotensin II antagonists which block AT1 and AT2 receptors.
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What is the mechanism of action of Sildenafil? what is its effect?
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Sildenafil inhibits the phosphodiesterase which breaks down NO-induced cGMP, increasing cGMP levels.
Sildenafil is used for the treatment of erectile dysfunction. |
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Which drugs are given by IV?
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Aminoglycosides
Vancomycin Amphotericin B |
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Which drugs are not safe for children?
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Tetracycline under 8y
Doxycycline under 8y Fluoroquinolones under 18y SMX under 2mo |
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Which drugs are CYP450 inducers?
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Rifampin
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Which drugs are CYP-450 inhibitors?
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Azoles
Erythromycin |
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Which drugs are safe for pregnant women?
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Penicillins
Cephalosporins Vancomycin Erythromycin Clindamycin Amphotericin B Acyclovir Paramomycin (PO) |
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Which antibacterial drugs are teratogenic?
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Aminoglycosides (IV)
Tetracyclines TMP-SMX Fluoroquinolones |
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What is the toxicity of penicillins?
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Hypersensitivity reactions
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What is the toxicity of cephalosporins?
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Hypersensitivity reactions
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Which antibacterial drugs cause hypersensitivity reactions?
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Penicillins (common)
Cepahlosporins (rare) Vancomycin (red man syndrome) Sulfamethoxazole (Stevens-Johnson Syndrome) Rifampin |
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What is the toxicity of Aminoglycosides?
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Nephrotoxicity (ATN)
Ototoxicity (cochlear=irreversible, vestibular=reversible) |
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Which antibacterial drugs cause nephrotoxicity?
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Aminoglycosides (ATN)
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Which antibacterial drugs cause ototoxicity?
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Aminoglycosides (cochlear=irreversible, vestibular=reversible)
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Which antibacterial drugs cause hepatitis? What are the risk factors?
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Rifampin (alcoholics, >50yo)
Isoniazid (alcoholics, >50yo) Tetracyclines (pregnant women) |
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What is the toxicity of Isoniazid? Who are at risk?
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Hepatitis (alcoholics, over 50yo)
Peripheral neuropathy (slow acetylators) |
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What is the toxicity of Rifampin? Who is at risk?
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Hepatitis (alcoholic or over 50)
Hypersensitivity Reddish-orange saliva, tears, urine CYP induction |
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Which antibacterial drugs cause phototoxicity?
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Tetracyclines
Fluoroquinolones |
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What is the toxicity of Tetracyclines?
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Teeth discoloration/hypoplasia
Temporary growth stunting Phototoxicity Hepatitis (pregnant women) |
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Which antibacterial drugs cause kernicterus?
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Sulfamethoxazole
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What is the toxicity of Sulfamethoxazole?
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Stevens-Johnson Syndrome
Kernicterus |
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Which antibacterial drugs cause arthropathy?
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Fluoroquinolones
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What is the toxicity of Fluoroquinolones?
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Phototoxicity
Arthropathy |
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Which antibacterial drugs cause peripheral neuropathy? Who is at risk?
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Isoniazid (slow acetylators)
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What is the treatment for Isoniazid-induced peripheral neuropathy?
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Pyridoxine (Vitamin B6)
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Which antibacterial drugs cause optic neuritis?
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Ethambutol
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What is the toxicity of Ethambutol?
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Optic neuritis
Acute gout |
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What is the toxicity of Pyrazinamide?
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Acute gout
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Which antibacterial drugs cause acute gout?
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Ethambutol
Pyrazinamide |
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How is renal toxicity not increased and therapeutic effect preserved with once-daily high dosing of aminoglyclosides?
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Once-daily high dosing decreases the overall time during which serum levels are above the threshold for toxicity. High doses saturate the Aminoglycoside receptors in the proximal renal tubules at high doses and efflux out when the doses fall.
Since Aminoglycosides bind irreversibly to the 30s subunit of bacterial ribosomes, the initial bactericidal effect becomes bacteriostatic once the serum levels decrease. |
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What is the combination therapy for tuberculosis?
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Isoniazid + Rifampin (9-12mo)
Isoniazid + Rifampin (6mo) + Pyrazinamide (first 2mo) Rifampin + Isoniazid + Pyrazinamide + Ethambutol or Streptomycin (to kill Isoniazid/Rifampin resistant isolates) |
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What is the mechanism of action of Isoniazid?
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Isoniazid is activated by the katG gene product Catalase Peroxidase, generates free radicals, and inhibits mycolic acid synthesis.
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What is the mechanism of action of Rifampin?
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Rifampin binds to the b-subunit of RNA Polymerase, preventing binding of RNA Polymerase to DNA, inhibiting transcription.
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How does resistance to Rifampin develop?
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Mutations in the b-subunit of RNA polymerase.
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How does resistance to Isoniazid develop?
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Mutations in the katG gene and its product: Catalse Peroxidase
Increased neutralization of free radicals |
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How does Isoniazid cause hepatitis? What increases the risk of this toxicity?
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Isoniazid is first acetylated in a Phase II reaction. Much of the metabolite is excreted in the kidney.
Some of the metabolite undergoes Phase I oxidative cleavage by CYP2E1 (activated by chronic alcohol use), producing acetylhydrazine which causes liver necrosis. |
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What activates CYP2E1? What is the clinical significance of this?
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Chronic alcohol use activates CYP2E1, which oxidatively cleave the inactive metabolites of Isoniazid to acetylhydrazine which cause liver necrosis.
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Who are at high risk of Isoniazid-induced hepatitis?
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Alcoholics
Pregnant women |
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To whom is Isoniazid given prophylactically?
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Patients under 35 with +PPD test.
Usually not given to patients over 50. Always given to high risk patients (immunocompromised, HIV+, close contacts of infecteds including children), regardless of age. |
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Which patients are at high risk for Isoniazid-induced peripheral neuropathy? Why? How is it treated?
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Slow acetylators because Isoniazid has a longer T1/2 and reacts with Pyridoxal Phosphate (Vitamin B6) to produce hydrazone, which is excreted by the kidneys, resulting in a pyridoxine deficiency and peripheral neuropathy.
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Slow-acetylators have a higher risk for what toxic effect of Isoniazid? Why? How is it treated?
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Isoniazid has a longer T1/2 in slow acetylators and reactions with Pyridoxal Phosphate (Vitamin B6) to produce hydrazone, which is excreted by the kidneys, resulting in a pyridoxine deficiency and peripheral neuropathy.
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Which drug causes patients to lose the ability to discriminate between red and green?
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Ethambutol
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How do Pyrazinamide and Ethambutol increase the risk of gouty attacks?
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Pyrazinamide and Ethambutol block tubule secretion of uric acid into the urine.
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How do penicillins, cephalosporins, and vancomycin interact with aminoglycosides.
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Penicillins, cephalosporins, and gentamicin make pores in the bacterial cell wall through which gentamicin can penetrate.
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How does Amphotericin B interact synergistically with Flucytosine?
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Amphotericin B makes pores in the fungal cell membrane, through which Flucytosine can penetrate.
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How do erythromycin, antifungal azoles, and metronidazole interact with warfarin and Cyclosporin A?
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Erythromycin, fungal azoles, and metronidazole all inhibit CYP450, increasing the toxicity of warfarin and cyclosporin A.
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How does Rifampin and Isoniazid interact with Cyclosporin A, Warfarin, and antifungal azoles.
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Rifampin and Isoniazid induce CYP450, increasing the metabolism of Cyclosporin A, Warfarin, and antifungal azoles and decreasing their effectiveness.
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How does aspirin and sulfamethoxazole interact with methotrexate and warfarin?
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Aspirin and sulfamethoxazole displace warfarin and methotrexate from albumin, increasing their plasma levels and toxicity.
Sulfamethoxazole also inhibits CYP450, increasing the toxicity of warfarin. |
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Which ingested products interact with tetracyclines and fluoroquinolones? How?
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Milk products and antacids contain divalent and trivalent cations which chelate tetracyclines and fluoroquinolones, decreasing absorption.
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What is the treatment of Enterocccus faecalis?
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Ampicillin + Gentamicin
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What enzyme does SMX inhibit? What compound levels does it decrease?
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SMX competes with PABA, inhibiting Dihydropterate Synthase and decreasing levels of dihydrofolic acid.
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What enzyme does TMP inhibit? What compound levels does it decrease?
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TMP inhibits Dihydrofolate Reductase, decreasing levels of tetrahydrofolic acid.
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What is the mechanism of action of TMP-SMX?
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SMX inhibits dihydropterate synthase, decreasing dihydrofolic acid levels.
TMP inhibits dihydrofolate reductase, dereasing levels of tetrahydrofolate. This sequential, synergistic inhibition inhibits purine synthesis. |
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How do fluoroquinolones interact with caffeine and theophylline?
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Fluoroquinolones inhibit CYP1A, increasing the plasma levels of caffeine and theophylline, possibly leading to seizures.
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What are the contraindications of tetracyclines?
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Children <8
Pregnant women Breastfeeding mothers |
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What are the contraindications of fluoroquinolones?
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Children <18
Pregnant women Breastfeeding women |
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What are the contraindications of TMP-SMX?
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Neonates <2mo
Pregnant women (3rd trimester) Breastfeeding mothers |
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What are the contraindications of erythromycin? What should it be replaced with for pneumonia?
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Impaired liver function
Erythromycin should be replaced with doxycycline for the treatment of pneumonia in patients with impaired liver function. |
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What are the contraindications of Isoniazid and Rifampin?
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Hepatic dysfunction
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What is the empiric therapy for middle ear infection? What if the infection gets better then worse? What if diarrhea occurs?
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Drug of choice: Amoxicillin
If gets better then worse: Amoxicillin + Clavulanate If diarrhea occurs: Cefprozil or Cefuroxime (2nd gen) |
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What is the empiric therapy for surgical prophylaxis? What if the patient is allergic? What if there is MRSA present?
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Drug of choice: Cefazolin (1st gen)
If allergic: Vancomycin If MRSA is present: Vancomycin |
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What is the empiric therapy for UTI? What if a rash develops? If pregnant?
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Drug of choice: TMP-SMX
If rash: Fluoroquinolones If pregnant: Cephalexin (1st gen) |
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What is the bacterial coverage of cephalosporins?
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1st gen: PEcK
2nd gen: HENPEcK 3rd gen: P. aeruginosa |
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What is the mechanism of action of Amantadine and Rimantadine?
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Amantadine and Rimantadine block the M2 ion channel of Influenza A Virus, preventing viral uncoating.
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Which antiviral drug is more lipophilic, enters the CSF, and is excreted unchanged compared to its analog?
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Amantadine is more lipophilic, enters the CSF, and is excreted unchanged by the kidneys.
Rimantadine is less lipophilic, does not enter the CSF, and is inactivated by the liver before being excreted by the kidneys. |
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Compare the side effects of Amantadine and Rimantadine
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Amantadine causes more CNS effects especially in the elderly than Rimantadine.
Both are Class C teratogens |
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What are the clinical uses of Amantadine and Rimantadine?
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Amantadine and Rimantadine are used for the treatment (if given within 48h) and prevention of Influenza A.
Amantadine is also used for Parkinson's disease. |
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What is the mechanism of action of Oseltamivir?
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Oseltamivir inhibits neuraminidase on Influenza A and B Viruses, inhibiting virus release.
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Describe the activation and elimination of Oseltamivir?
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Oseltamivir is an ethyl ester prodrug activated in the liver to a carboxylate. Oseltamivir is excreted by the kidneys in its active form.
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What are the side effects of Oseltamivir?
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N/V
Cass C teratogen |
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What are the clinical uses of Oseltamivir?
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Oseltamivir is used for the prevention and treatment of Influenza A and B Viruses, including H1N1.
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What is the mechanism of activation and action of Ribavirin?
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Ribavirin is activated by host NK to RibavirinMP. RibavirinMP inhibits Inosine Monophosphate Dehydrogenase, decreasing synthesis of GTP, vRNA, and DNA. RibavirinMP is phosphorylated to RibavirinTP, which inhibits RNA Polymerase of Influenza A and B Viruses.
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Describe the route of administration and half-life of Ribavirin?
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Aerosol
PO IV T1/2 erythrocytes: 40d T1/2 tissues: 12d |
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What are the side effects of Ribavirin?
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Aerosol: Cardiac arrest, apnea, pneumothorax
PO/IV: Hemolytic anemia Class X teratogen |
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What are the clinical uses of Ribavirin?
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Aerosol: Respiratory Syncytial Virus (neonates)
PO: +IFN2a for HCV (6-12mo) IV: Lassa fever |
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How does Ribavirin cause hemolytic anemia?
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Ribavirin is transported into erythrocytes via an inosine-sensitive nucleoside transporter. Ribavirin is phosphorylated to RibavirinTP and accumulates in erythrocytes, inhibiting generation of ATP and NADPH, decreasing levels of GSH, leading to oxidative membrane damage.
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What is the mechanism of activation and action of Acyclovir?
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Acyclovir is selectively activated by VSV/HSV Thymidine Kinase to AcyclovirTP. AcyclovirTP inhibits viral DNA polymerase and incorporates into vDNA as a guanosine analog, causing chain termination.
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Describe the route of administration, CSF penetration, and elimination of acyclovir?
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Acyclovir is administered PO, IV, or topically.
Acyclovir penetrates the CSF. Acyclovir is eliminated by the kidneys. |
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What are the side effects of acyclovir?
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Acyclovir causes few side effects
Class B non-teratogen |
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What are the clinical uses of acyclovir?
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HSV: Herpes labialis, herpes genitalis, herpes encephalitis
VSV: chicken pox, shingles Prophylaxis for immunosuppressed |
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Describe the mechanism of activation and action of Vidarabine
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Vidarabine is non-selectively activated by host kinases to VidarabineTP. VidarabineTP inhibits viral DNA polymerase and is incorporated into DNA as an adenosine analog, causing chain termination.
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Describe the administration and inactivation of Vidarabine?
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Vidarabine is relatively insoluble and must be administered with large doses of IV fluid. It is rapidly deactivated. It can be used topically as well.
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What are the side effects of vidarabine?
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Vidarabine causes encephalopathy (headache, dizziness, hallucinations, coma) since deaminases are low in the CSF.
Class C teratogen |
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What are the clinical uses of Vidarabine?
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Vidarabine is used topically for herpes keratitis.
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Describe the mechanism of activation and action of Ganciclovir?
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Ganciclovir is partially selectively activated by CMV deoxyguanosine kinases, VSV/HSV thymidine kinases, and infection-induced host kinases to GanciclovirTP.
Ganciclovir TP inhibits viral DNA polymerase and is incorporated as a guanosine analog, slowing chain elongation. |
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How is Ganciclovir administered and eliminated?
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Ganiclovir is administered IV and eliminated by the kidneys.
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What are the side effects of Ganciclovir?
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Ganciclovir causes leukopenia and thrombocytopenia.
Class C teratogen |
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What are the clinical uses of Ganciclovir?
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Ganciclovir is used to treat cytomegalic retinitis.
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What is the mechanism of action of Amphotericin B? Is it fungicidal of fungistatic?
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Amphotericin binds to ergosterol, creating pores in fungal membrane. It is fungicidal.
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How is Amphotericin B administered? Does it penetrate the CSF?
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Amphotericin B is not orally absorbed and does not penetrate the CSF. It is given IV or intrathecally.
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What are the side effects of Amphotericin B? How are these reduced?
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Amphotericin B cause infusion-related toxicity and renal toxicity. Renal toxicity is reduced with saline pre-infusion and liposomal preparations.
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What are the clinical uses of Amphotericin B?
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Broad spectrum antifungal drug for life-threatening infections
Only systemic antifungal safe for pregnant women. |
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What is the mechanism of action of Flucytosine?
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Flucytosine enters fungal cells via permease and is converted to 5-Fluorouracil which inhibits thymdilate synthase and RNA synthesis.
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Is flucytosine protein-bound or free? Does it enter the CSF? How is it eliminated?
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Flucytosine has low protein-binding.
Flucytosine enters the CS. Flucytosine is excreted by the kidneys. |
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What are the side effects of Flucytosine? Who is it not used for?
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Flucytosine causes myelosuppression and is not used for AIDS or BM-depressed patients.
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How is Flucytosine used in therapy?
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Not used as a single agent since resistance devleops quickly.
Flucytosine is combined with Amphotericin B. |
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What is the mechanism of action of Ketoconazole, Itraconazole, and Fluconazole?
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Ketoconazole, Itraconazole, and Fluconazole bind to and inactivate fungal CYP450, inhibiting ergosterol synthesis.
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How are ketoconazole and itraconazole administered? What affects their adsorption? Do they enter the CSF?
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Ketoconazole and Itraconazole are given PO. Antacids reduce the acidity of the stomach and reduce their adsorption. They do not penetrate the CSF.
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How is Fluconazole administered? Does it enter the CSF? How is it excreted?
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Fluconazole is administered PO or IV.
Fluconazole penetrates the CSF. Fluconazole is excreted by the kidneys. |
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What are the side effects of ketoconazole? How does this occur?
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Ketoconazole inhibits CYP450 mediated synthesis of sex steroid synthesis causing impotence and infertility.
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What are the side effects of Itraconazole and Fluconazole?
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Itraconazole and Fluconazole inhibbit CYP450.
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What are the clinical uses of Fluconazole?
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Fluconazole is used to treat fungal meningeal infections, fungal UTI, and as prophylaxis.
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What are the clinical uses of ketoconazole?
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Ketoconazole is used for mucocutaneous candidiasis and nonmeningeal coccidioidomycosis.
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Which fungus is Itraconazole used to treat?
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Aspergillus
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What is the drug of choice for severe candidiasis with or without neutropenia? For mild or moderate candidiasis?
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Severe candidiasis with neutropenia is treated with Amphotericin B IV.
Severe candidiasis without neutropenia is treated with Amphotericin B or fluconazole (less toxic) Mild or moderate candidiasis is treated with fluconazole or itraconazole. |
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What is the drug of choice for nonmeningeal cryptococcosis?
Meningeal cryptococcosis? If bone marrow is depressed? Mild or moderate cryptococcosis? |
Nonmeningeal cryptococcosis: Amphotericin B
Meningeal cryptococcosis: Amphotericin B + Flucytosine If BM-depressed: Amphotericin B intrathecal with fluconazole follow-up. Mild or moderate: Fluconazole or itraconazole |
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What is the drug of choice for nonmeningeal coccidioidomycosis?
Meningeal coccidioidomycosis? If bone marrow is depressed? Mild or moderate coccidioidomycosis? |
Nonmeningeal coccidioidomycosis: Amphotericin B IV
Meningeal coccidioidomycosis: Amphotericin B + Flucytosine If BM-depressed: Amphotericin B + Fluconazole follow-up Mild or moderate: Fluconazole or itraconazole. |
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What is the drug of choice for invasive Aspergillosis?
Mild or moderate Aspergillosis |
Invasive Aspergillosis: Amphotericin B IV
Mild or moderate Aspergillosis: Itraconazole, fluconazole |
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What is the drug of choice for severe histoplasmosis?
Mild or moderate histoplasmosis? |
Severe histoplasmosis: Amphotericin B
Mild or moderate histoplasmosis: Itraconazole, fluconazole |
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What is the drug of choice for severe Blastomycosis?
Mild or moderate blastomycosis? |
Severe blastomycosis: Amphotericin B
Mild or moderate Blastomycosis: Itraconazole or Ketoconazole |
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What is the drug of choice for antifungal prophylaxis? Why?
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Fluconazole for AIDS or bone marrow-depressed patients. Fluconazole has a wide therapeutic index.
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Which drugs decrease absorption of Ketoconazole and itraconazole?
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Antacids
H2 blockers (Cimetidine (toxic), Nizantidine, Famotidine, Ranitidine) |
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Why is fluconazole useful for treating fungal UTIs?
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Fluconazole is excreted in urine in its active form.
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What is the toxicity of Doxorubicin? How is it caused? What are additional risk factors?
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Cardiomyopathy
Doxorubicin forms oxygen radicals. Risk factors include total dose >500mg/m^2, radiotherapy to the heart, and cyclophosphamide co-treatment. |
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What is the toxicity of cyclophosphamide? How is it caused? How is it treated?
|
Hemorrhagic cysticis
Cyclophosphamide is metabolized to acrolein which is toxic to the bladder. This is treated with thiol agents, mesna, or N-acetylcysteine. |
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What is the toxicity of Bleomycin? How is it caused? What are additional risk factors?
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Pulmonary fibrosis
Bleomycin undergoes a redox cycle, forming oxygen radicals. It is not treated with 100% O2. Additional risk factors include radiotherapy to the chest, renal failure, and oxygen therapy. |
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What is the toxicity of Busulfan? How is it caused? How is it treated?
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Pulmonary fibrosis
Busulfan accumulates and binds to proteins in the lung. It is treated with 100% O2. |
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What is the toxicity of Cisplatin?
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Ototoxicity, Nephrotoxicity
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What is the toxicity of Vincristine? How is it treated?
|
Peripheral neuropathy
Vincristine can be replaced with vinblastine. |
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What is the toxicity of cytarabine?
|
Cerebral dysfunction
Cytarabine is not deaminated in the CSF and persists. |
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What are the clinical uses of synthetic nitrosoureas? Why?
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Synthetic nitrosoureas (Carmustine, Lomustine, Semustine) can be used to treat brain tumors since they are lipophilic and can cross the BBB.
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What is the clinical use of natural nitrosoureas? Why?
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Natural nitrosoureas (Streptozotocin) are hydrophilic and do not cross the BBB but are used to treat pancreatic islet cell carcinomas.
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How is estrogen synthesized in postmenopausal women? What is a therapeutic way to target this?
|
The adrenal cortex converts cholesterol to androstenedione.
Adipose tissue aromatase converts androstenedione to estrone. Breast tissue converts estrone to estradiol. Anastrozole and Letrozole target aromatase in adipose tissue, decreasing synthesis of estrogen in postmenopausal women. |
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What is the mechanism of action of Anastrozole and Letrozole?
|
Anastrozole and Letrozole inhibit aromatase in the adipose tissue, decreasing synthesis of estrogen in postmenopausal women.
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What is the hormonal therapy for prostate cancer?
|
1. Leuprolide, Goserelin (LRHR agonists) w/ or w/o flutamide.
2. Diethylstilbesterol is as efficient as LHRH agonists, but causes cardiac problems (limited use) 3. Flutamide (antiandrogen) is used with LHRH only, never alone. |
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What is the mechanism of action of leuprolide and goserelin?
|
Leuprolide and Goserelin are LHRH agonists which desensitize LHRH-Receptors on the pituitary, leading to pharmacological castration.
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What is the mechanism of action of Flutamide? How is it administered?
|
Flutamide (antiandrogen) and its metabolic product antagonize testosterone receptors but must be given at very high dose to overcome testosterone's higher affinity. Testosterone receptor antagonism of the Hypothalamus increases LHRH and testosterone, therefore Flutamide must be given with leuprolide or goserelin.
Flutamide is effective in antagonizing hormone-independent adrenal cortex-produced androgens. |
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How does Leucovorin and high dose methotrexate work?
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Leucovorin enters normal cells through normal folate transporters and protects normal cell DHFR. Leucovorin does not enter cancer cell low folate transporters.
High dose methotrexate passively diffuses into cancer and normal cells. Cancer cells polyglutamate methotrexate, stopping efflux. Normal cells do not stop efflux and are protected by leucovorin. |
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How is dose adjusted for slow metabolizers?
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Loading dose and maintenance dose are decreased.
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How is dose adjusted for fast metabolizers?
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Maintenance dose only is increased
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Which amebicides target cysts of E. histolytica?
|
Diloxanide furoate
Iodoquinol Paramomycin |
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Which amebicides target tissue infections of E. histolytica?
|
Metronidazole
Chloroquine (serious infections) |
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What is the mechanism of action of metronidazole?
|
Metronidazole undergoes an anaerobic redox cycle with fungal Pyruvate Ferridoxin Reductase, causing DNA and protein damage.
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What is the adsorption pattern and teratogenicity of Diloxanide?
|
90% absorbed but inactivated, 10% stays in lumen.
Small amount is teratogenic. |
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What is the adsorption pattern and teratogenicity of Iodoquinol?
|
10% absorbed, 90% stays in lumen
Absorbed amount is teratogenic |
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What is the adsorption pattern and teratogenicity of Paramomycin?
|
100% stays in lumen
Safe for pregnant women |
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What is the treatment for non-invasive Aspergillus?
|
Itraconazole
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Synthesis of which nucleotide family requires PRPP Amidotransferase?
|
Purine
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What is the regulation of PRPP Amidotransferase?
|
IMP, AMP, and GMP negatively feedback
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The 1 C pool is required for what metabolic pathways?
|
Purine de novo synthesis
Homocysteine/Methionine recycling dUMP-->dTMP |
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Synthesis of which nucleotide family has the sugar forming first and then the base being built onto it?
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Purine
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Synthesis of which nucleotide family requires Carbamoyl Phosphate Synthetase II?
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Pyrimidine
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What is the regulation of CPS II?
|
PRPP positively induces
UTP negatively inhibits |
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Which enzyme converts nucleosides into nucleotides? What does it use?
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Nucleoside kinase using 1 ATP
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Which enzyme converts dUMP into dTMP? What does it use?
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Thymidylate Synthase using Methylene-THFA
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Which enzyme converts NDP into dNDP?
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Ribonucleotide reductase
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Which enzyme converts NMP into NDP and NTP?
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Nucleoside kinase
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An increase in the activity of which enzyme would increase the risk of gout?
|
Xanthine Oxidase
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Which drug decreases the risk of gout? What is its mechanism of action?
|
Allopurinol inhibits Xanthine Oxidase
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A deficiency in HGPRTase is known as what? What metabolic pathway is deficient? How does this lead to gout?
|
Lesch-Nyman Syndrome: no HGPRTase to perform salvage pathway of base + PRPP --> Nucloetide + PPi
Since purines are not being salvaged, they must be remade de novo. Purines that would be salvaged are being degraded into uric acid. |
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Which enzyme converts bases and PRPP into nucleotides and PPi?
|
Phosphoribosyl Transferases (HGPRTase)
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What is Lesch-Nyman Syndrome?
|
Lesch-Nyman Syndrome is a deficiency in HGPRTase where the salvage pathway of base + PRPP --> nucleotide + PPi is not functional
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What is Orotic Aciduria? What causes it?
|
A defect in pyrimidine de novo synthesis causes an increase in OA, a pyrimidine de novo synthesis intermediate
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OA is an intermediate in de novo synthesis of which nucleotide family?
|
Pyrimidine
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IMP is an intermediate in de novo synthesis of which nucleotide family?
|
Purine
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How are purines degraded?
|
The purine ring is oxidized to uric acid, not cleaved.
Xanthine Oxidase converts HX to X to Uric acid |
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How are pyrimidines degraded?
|
The ring is broken down into CO2, NH3, and AAs
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