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228 Cards in this Set
- Front
- Back
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How far back in history (provide a date) has alcohol been known about and used?
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6400 BC
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Modern style grape fermentation dates back to what date range?
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300-400 BC
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During the middle ages, how was alcohol viewed?
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Alcohol was a remedy for all diseases, and whisky was known as the "water of life."
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How valuable is alcohol therpeutically?
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Not very valuable at all.
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Classically, what type of problems (non-medically specific) develop in a chronic alcoholic?
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Various medical and legal problems.
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What is the main difference between fermented alcohol products and distilled alcohol products?
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Fermented products are made naturally (wines, beers), while distilled products are physically altered fermentations in order to achieve a greater alcohol concentration.
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How are wines fermented?
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Yeast, in the presence of water and sugar, will recombine those sugars into alcohol and CO2.
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How are American beers fermented?
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Barley is malted to have grain sprouts, and these sprouts contain sugars, enzymes, and water. This eventually results in the formation of alcohol and CO2.
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How are Foreign beers fermented?
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Instead of using barley in the fermentation, cereal grains are used.
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In the USA, distilled alcohol is labeled in strengths referred to as "proof." Explain this labeling.
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An alcohol's "proof" is labeled as double the percent (v/v) ethanol present.
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While the public views alcohol as a(n) _________, pharmacologically it is a(n) _________.
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Stimulant; depressant
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What effect will low concentrations of alcohol have on excitatory neurons?
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At low levels, alcohol will enhance these neurons
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Any stimulation that occurs with alcohol occurs how?
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Stimulation may occur due to the depression of inhibitory control mechanisms in the brain.
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What are the first mental processes effected by ingesting ethanol?
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Those mental processes that are dependent on training and previous experience. The persons concentration is dulled and lost.
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What are the psychic effects of ingesting ethanol?
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A persons personality becomes expansive and vivacious, with uncontrolled moodswings and outbursts. These changes are associated with sensory and motor disturbances.
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With severe intoxication, ethanol will result in this right before death.
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Anesthesia. But the lethal dose is too close to the anesthetizing dose.
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What are some general effects of ethanol as they relate to increasing BAL?
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Lowered alertness, pleasant feelings, psychic and personality changes, and disruption of performance.
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What does "disruption of performance" refer to in regards to an increasing BAL?
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Simple visual, motor, and visio-motor performances are lowered due to the decline in ability to make decisions.
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In 'abstainers' at what BAL do we start to see the general effects of alcohol as they relate to increasing BAL?
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0.05% EtOH
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In 'moderate drinkers' at what BAL do we start to see the general effects of alcohol as they relate to increasing BAL?
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0.07% EtOH
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In 'heavy drinkers' at what BAL do we start to see the general effects of alcohol as they relate to increasing BAL?
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0.1% EtOH
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Why do heavy drinkers require a greater EtOH concentration before we see the BAL associated general effects of alcohol?
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Heavy drinkers develop a behavioral and CNS tolerance to alcohol. They are also better motivated to conceal the alcohol induced impairment, and they have more practice at it. It is not due to a faster EtOH metabolism.
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Which 'D' words describe a person who has a BAL of 0.05%?
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Dashing and Debonair
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Which 'D' words describe a person who has a BAL of 0.1%?
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Dangerous and Devilish
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Which 'D' words describe a person who has a BAL of 0.2%?
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Dizzy and Disturbing
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Which 'D' words describe a person who has a BAL of 0.25%?
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Disgusting
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Which 'D' words describe a person who has a BAL of 0.30%?
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Delirious and Disoriented (Surely Drunk)
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Which 'D' words describe a person who has a BAL of 0.35%?
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Dead Drunk
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Which 'D' words describe a person who has a BAL of 0.60%?
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Dead
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Which effects would we see in a person whose BAL is 0.1-0.15%?
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We would see a consistent decline in motor funcitons, vomiting (if drinking fast, when drinking slow, we see a depression of the vomit reflex)
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Which effects would we see in a person whose BAL is 0.2%?
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We would see a marked depression in sensory and motor capabilities.
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Which effects would we see in a person whose BAL is 0.25%?
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We would see a severe disturbance in motor functions and sensory perception.
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Which effects would we see in a person whose BAL is 0.3%?
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We would see a person who has almost no comprehension of the world around them, but they would still be conscious.
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Which effects would we see in a person whose BAL is 0.35%?
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We might see the person unconscious, since this level the surgical anesthesia level. Also, it is the first level at which a person may die from alcohol ingestion as it is the LD10 level.
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Which effects would we see in a person whose BAL is 0.4%?
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We would have a 50/50 chance at seeing the person dead, since this level is the LD50. This is because of respiratory depression.
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Which effects would we see in a person whose BAL is 0.6%?
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We would most likely see the person dead.
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What type of brain damage do we see in living chronic alcoholics upon a medical tests and a CT/MRI?
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We see significant tissue loss due to membrane fluidization, vitamin (Niacin) deficiency. We would also see encephalopathy and an abnormal EEG test.
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What type of observable brain damage do we see in living chronic alcoholics in day-to-day interactions?
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We would see psychosis, dementia, global decline of intellect, difficulty in swallowing, and impaired problem solving abilities.
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What type of brain damage do we see in chronic alcoholics upon a medical autopsy?
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Enlarged brain ventricles and widened fissures in the cortex.
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What is Wernicke's Syndrome?
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A long term CNS effect of EtOH that has symptoms of confusion, ataxia, and abnormal eye movement. It is also associated with a thiamine (VitB1) deficiency.
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Can Wernicke's syndrome be corrected?
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Yes, it can be corrected nutritionally.
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What is Korsakoff's Psychosis?
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A long term CNS effect of EtOH that has symptoms of an inability to remember recent events or new information.
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Can Korsakoff's Psychosis be corrected?
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No, it is irreversible.
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What is Wernike-Korsakoff's syndrome?
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A syndrome combining Wernike's syndrome and Korsakoff's psychosis.
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What are some symptoms of Wernike-Korsakoff's syndrome?
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Confusion, ataxia, abnormal eye movement, and an inability to remember recent events or new information.
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Is Wernike-Korsakoff's syndrome reversible?
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Paritally, since Wernike's syndrome is reversible with nutritional supplement.
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How was EtOH classicaly thought to have its mechanism of action in the CNS?
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It was thought that it dissolves in the lipids of membranes, and increases the fluidity of the membranes too much disturbing functions of proteins and channels.
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How is EtOH thought to have its mechanism of action in the CNS in modern research?
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Alcohol is now found to have an effect on the exicatory neurons by inhibiting glutamate-activated ion currents. This effectively augments the inhibitory role that GABA plays on inhibitory neurons.
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What effects of EtOH do we see on respiration?
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EtOH will depress the ventialltory response to the presence of CO2. Moderate amounts will either stimulate or depress respiration. Severe intoxication leads to respiratory depression and death.
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What effects of EtOH do we see on sleep?
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When used at bedtime, EtOH decreases the time it takes to fall asleep, it increases 'deep sleep' time, and it decreases sleep disrutpions. Unfortunately, it will augment sleep apnea, and chronic alcoholics will find their sleep constantly interrupted.
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What effects does EtOH have on the CVS?
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Mild/Moderate doses increase pulse, vasoconstrict in vital organs, vasodialate in skin vessels, bring warming sensations, and may cause hypertenstion. Larger doses cause hypothermia. Chronically, we see cardiomyopathy.
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What effects does EtOH have on skeletal muscle?
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Large doses decrease muscular work due to CNS depression. Chronically, we will see increased levels on creatine phosphate in plasma and muscular damage. These effects may/may not be reversible.
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What effect does a stomach concentration of 10% EtOH have on GIT secretions?
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It stimulates gastric juice secretions by exciting the sensory endings in the buccal and gastric mucosa.
It also results in secretion of gastrin and histamine. |
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What effect does a stomach concentration of 20-40% EtOH have on GIT secretions?
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At this concentration, gastric secretions are inhibited and gastric activity is depressed.
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What effect does a stomach concentration of over 40% EtOH have on GIT secretions?
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At this concentration the EtOH is very irritating to the mucosa, and we will probably see inflammation as erosive gastritis.
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What effects do alcohol have on the GIT at very high (intoxicating doses)?
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We will see cessation of most/all gastric secretion, a delay in absorption, and vomiting due to local irritation.
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What effects do alcohol have on the pancreas in the GIT?
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The pancreatic duct will be obstructed, and we will see inflammation of the pancreas, pancreatitis.
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What nutritional effects will we see on the GIT as a result of EtOH intoxication?
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We will see vitamin deficiencies and slowed absorption. These effects are secondary to the primary GIT effects and to liver dysfunction.
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Are there any effects seen with acute alcohol intoxication on the liver?
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No, mostly effects are seen with chronic intoxication.
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What are some effects we see on the liver with chronic drinkers?
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Dose dependent damage that leads to an irreversible cirrhosis (fibrosis) visible by jaundice and toxin accumulation. It will take about 10 years of steady, intense, chronic drinking to see cirrhosis. Malnutrition will only make it worse. It is the 7th leading cause of death in the US.
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By what mechanism do we see chronic effects of alcoholism in the liver?
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EtOH is metabolized by mixed fucniton oxidases, which convert it into acetaldehyde. Acetaldehyde complexes with proteins, and therefore inhibits several enzymatic functions. We also see these effects due to peroxidation of mitochondrial membranes and a glutathione depletion.
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Alcohol is known to be potentially carcinogenic due to an increased prevalance of cancers of what regions?
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Mouth, tongue, pharynx, larynx, esophagus, stomach, pancreas, colon, and rectum.
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What effects do alcohol have on fetal development? Basically, describe Fetal Alcohol Syndrome and how it happens.
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Fetal Alcohol Syndrome (small heads, small eyes, short nose, hypoplastic upper lip, CNS dysfunction, slow growth and other variable malformations) due to the effects of acetaldehyde on embryonic cellular proliferation and placental injury.
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What are some sexual, acute effects of alcohol?
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Aggressive sexual behavior, but a decrease in ability to perform sexually, and a decrease in sexual responsiveness.
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What are some sexual, chronic effects of alcohol in males?
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We would see impotence, sterility (Testicular atrophy), and feminization due to decreased testosterone production and an increase in testosterone metabolism.
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What effects of alcohol do we see on the kidneys?
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We will see a diuretic effect due to inhibition of ADH secretion and due to decrease in renal tubular reabsorption.
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What biogenic effects of alcohol do we see with the ingestion of EtOH?
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An increase in catecholamine release, which causes increased catecholamines in the blood, which may cause transient hyperglycemia, pupillary dialation, and an increase in blood pressure.
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What are two main ways alcohol is absorbed into the body?
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By ingestion or inhalation, both of which absorb alcohol well. Ingestion provides for rapid absorption. Inhalation may be fatal.
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How much time does it take after the last drink to see the maximal BAL?
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30-90 minutes depending on the factors that effect stomach absorption.
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What are some factors affecting stomach absorption of EtOH, and how do they affect the absorption (increase or decrease)?
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The presence of food (delays), Plain water (delays), carbonated beverages (increase)
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What is the key principle to remember about the distribution of alcohol?
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It does not distribute into fatty tissues, therefore 2 people of the same weight will find that the "fatter" of the two will have a higher BAL.
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How much of ingested alcohol is metabolized in the liver by alcohol dehydrogenase?
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90-98% is oxidized here into acetaldehyde.
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What is acetaldehyde then converted into?
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Acetyl CoA
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How is acetaldehyde converted into the next metabolic product?
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It is converted into Acetyl CoA by aldehyde dehydrogenase.
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Of what use is Acetyl CoA?
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Acetyl CoA is used in the citric acid cycle for many anabolic reactions including the synthesis of cholesterol and fatty acids.
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What is the rate of alcohol metabolism?
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0.25-0.30oz./hour
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Where is some of the other 2-10% of ethanol metabolized?
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A portion of this remnant is metabolized by the hepatic MFO in the endoplasmic reticulum, and by the stomach alcohol dehydrogenase
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What type of kinetics does alcohol metabolism follow, and what does this mean?
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Alcohol metabolism follows zero-order kinetics, meaning that there it nothing you can do to sober up a person besides waiting for the enzyme to do its job.
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How toxic is acetaldehyde and what is it ultimately responsible for?
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Acetaldehyde is very toxic at 1/1000 the concentration of alcohol, it is responsible for the toxic effects we associate with alcohol.
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At the chronic exposure rate, how does alcohol metabolism affect the metabolism of other drugs?
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Chronic alcohol intake increases the amount of microsomal MFO effectively altering the metabolism of drugs that are metabolized by this route.
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What happens when heavy drinkers stop drinking?
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Alcohol disapears from the body, but we still see the high level of enzyme activity for about 4-8 weeks thereafter.
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How much alcohol is excreted in the unoxidized form in which organs? Relate the concentration of alcohol in expired air to that in the blood.
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2-10% of ethanol is released as unoxidized EtOH through the lungs and kidneys. The EtOH concentration in blood is 2100x greater in the blood than in the expiration.
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How much beer, spirit, or wine constitues one standard drink?
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1 can of beer (12 oz. @ 4.2% EtOH), 1 oz. of spirit (50% EtOH), or 1 glass of Wine (4 oz. @ 12% EtOH)
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If we assume the rate of alcohol metabolism is 0.25 oz./hour, how long does it take to metabolize one standard drink?
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(0.5oz/0.25oz./hour) = Two hours
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Having how many drinks every two hours will maintain a steady BAL?
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One drink every two hours.
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If you consume more than one drink every two hours, what happens to the BAL?
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It rises because the body only metabolizes one drink in two hours.
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Why are women more sensitive to the effects of alcohol than men?
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Women have a higher absorption rate than men, women have a greater distribution of fat than men, so they have a smaller volume of distribution, and stomach ADH is more active in men than women.
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Since women are more sensitive to the effects of EtOH, if a man and a woman have had the same amount of drinks, and if the man is dangerous and devilsh, then...
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The woman may be too dizzy and distrurbed to notice.
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What effect does alcohol have on CNS depressants?
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It is contraindicated since it is also a CNS depressant.
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What effect does alcohol have on Phenytoin?
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It reduces phenytoin clearance.
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What effect does alcohol have on tolbutamide and other hypoglycemics?
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It reduces their half-life
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What effect does alcohol have on acetaminophen?
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It increases the hepatoxicity of acetaminophen by increasing the amount of acetaminophen-reactive intermediates and by depleting glutathione.
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When taking alcohol with these drugs, unpleasant symptoms are produced.
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Metronidazole, oral hypoglycemics, and cephalosporins.
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What are some contraindications of alcohol ingestion?
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Hepatic diseases, GIT ulcers, Cardiomyopathy, pregnancy
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At which blood alcohol concentration would you be considered not under the influence for driving?
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BAL =< 0.05%
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At which BAL would you be considered with other factors do determine your legal intoxication when it comes to driving?
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0.05% < BAL < 0.10%
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At which BAL would a person be considered intoxicated and unable (legally) to drive?
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BAL >= 0.10%
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How much more likely are drivers to have a fatal accident when their BAL is between 0.1-0.15%?
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About 7x to 25x more likely, respectively.
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What is alcohol withdrawal syndrome? What might it be accompanied by?
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The revelation (within a few days of quitting drinking) of physical dependence and heavy alcohol use. It may be accompanied by the sensation of snakes or bugs crawling under the skin.
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What is Delerium Tremens?
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"Trembling Madness" in latin referring to alcohol withdrawal syndrome cases where at least stage 3 symptoms are seen.
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Can medical treatment be used in the treatment of alcohol withdrawal syndrome?
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Yes, it can be used (Diazepam) at stages 1 and 2 to prevent stages 3 and 4.
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Describe Stage 1 of alcohol withdrawal syndrome.
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Tremor, Excessive rapid heart beat, heavy sweating, loss of appetite, insomnia, nausea, and vomiting.
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Describe Stage 2 of alcohol withdrawal syndrome.
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Auditory, visual hallucinations, or a combination of both
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Describe Stage 3 of alcohol withdrawal syndrome.
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Delusions, disorientations, delerium, and amnesia
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Describe Stage 4 of alcohol withdrawal syndrome.
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Seizure
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How do you treat acute alcohol intoxication when the patient is comatose?
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Stomach lavage (pumping), hemodialysis
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How do you treat acute alcohol intoxication when the patient is not comatose?
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Wait for alcohol metabolization, only give sedatives to violent patients with great precaution
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What type of symptoms does acetaldehyde produce?
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Vasodialation, warmth, pulsing headache, respiratory difficulty, vomiting, sweating, chest pain, hypotension, vertigo, blurred vision
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What are two available treatments, not cures, for chronic alcoholism?
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Disulfiram and naltrexane
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What is disulfiram?
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A treatment, not cure, for chronic alcoholism that acts to help those who sincerely want to stop drinking. It essentially blocks the converting of acetaldehyde to its metabolites, increasing the maleffects of drinking, and effectively weaning people off of alcohol.
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What is naltrexane?
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A treatment, not cure, for chronic alcoholism that is an opioid agonist that acts to reduce the euphoric and reinforcing effects of alcohol.
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What are the pathological hallmarks of Alzheimer's disease?
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Amyloid plaques and neurofibrillary tangles
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What are the four main genetic 'causes' behind Alzheimer's disease?
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Mutations in the amyloid precursor protein (APP), Mutations in presenilins, apolipoprotein E4 allele, manipulations of the tau proteins.
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What is the amyloid precursor protein?
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A protein with 695, 751, or 770 amino acids whose gene is found on chromosome 21. It has three secretase sites, the beta, alpha, and gamma sites. It also has three secretases respectively.
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A cleavage of the amyloid precursor protein at which sites leads to increased b-amyloid formation?
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The beta and gamma cleavages lead to the formation of b-amyloids. Alpha cleavages result in neuroprotective functions.
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Mutations near which sites on the amyloid precursor protein are thought to result in Alzheimer's disease?
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Mutations near the beta and gamma secretase sites.
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What are the presenilins?
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Two separate proteins, one expressed early, one later, which enhance production of the b-amyloids when mutated.
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It is believed that presenilin 1 may function as what?
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A g-secretase or at least part of a protein complex that functions as a g-secretase.
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What is the Apolipoprotein E4 allele?
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The second most common of the common ApoE alleles found on chromosome 19 that codes for a lipoprotein transport molecule.
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Describe the Apolipoprotein E4 and how it functions.
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It binds normally to the LDL receptor, yet it is associated with elevated plasma cholesterol and an earlier onset of Alzheimer's.
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Describe the Apolipoprotein E2 and how it functions.
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It binds poorly to the LDL receptor, it is associated with hyperlipoproteinemia, but a later onset Alzheimer's disease.
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What are tau proteins?
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Microtubule-associated proteins that stabilize microtubules and they may become phosphorylated. Phosphorylated tau proteins result in the neurofibrillary tangles and general neuronal degeneration.
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What are the animal models useful for in Alzheimer's disease?
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They are useful for assesing effectiveness of new Alzheimer's treatments.
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What is the animal model in regards to Alzheimer's disease?
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Triple transgenic mice expressing mutant forms of the amyloid precursor protein, presenilin-1, apolipoprotein E4, and tau proteins demonstrated Alzheimer's pathologies and general neuronal degeneration.
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It is ultimately the mutations in the mutations of the amyloid precursor protein that result in the formation of these...
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Amyloid plaques
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It is ultimately the overphosphorylation of the tau proteins that result in the formation of these...
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Neurofibrillary tangles
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We see a significant loss of this in the cortex and hippocampus of Alzheimer's disease patients?
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Choline acetyltransferase due to the loss of neurons that produce acetylcholine
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What is the hypothesis behind the most common treatment of Alzheimer's disease?
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Due to the loss of acetylcholine, we will administer acetylcholinesterase inhibitors and/or muscarinic agonists.
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What are the four acetylcholinesterase inhibitors we discussed in class?
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Tacrine (cognex), Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Reminyl)
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Which of the acetylcholinesterase inhibitors takes the longest to reach peak levels?
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Donepezil (aricept)
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Which of the acetylcholinesterase inhibitors reaches peak levels quickest?
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Rivastigmine (Exelon) and Galantamine (Reminyl)
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Which of the acetylcholinesterase inhibitors is absorbed the most?
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Donepezil (aricept) at 100%, Galantamine (Reminyl) at 90%
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Which of the acetylcholinesterase inhibitors is absorbed the least?
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Tacrine (Cognex) at 5-30%, Rivastigmine (Exelon) at 36%
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What are the side effects of the acetylcholinesterase inhibitors?
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Nausea, vomiting, diarrhea, anorexia, fatigue, abdominal pain, and dyspepsia
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Which of the acetylcholinesterase inhibitors is a natural product isolated from the dafodil?
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Galantamine (Reminyl)
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What is the other type of drug used in the treatment of Alzheimers?
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Memantine (Namenda) which acts by antagonizing the NMDA glutamate receptor.
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What are some qualities about memantine (namenda)?
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Absorbed at 100%, peak levels reached 4-6 hours.
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What are some other therapies for Alzheimer's disease besides the acetylcholinesterase inhibitors and namenda?
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Anti-inflammatories, Amyloid-plaque formation prevention, muscarinic agonists, antioxidants, estrogen replacement therapy, and decrease risk for Alzheimer's
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Which anti-inflammatory drugs would you use to treat Alzheimer's disease?
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NSAIDs
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In treating Alzheimer's disease, how would you prevent amyloid plaque formation?
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Alzhemed. Or by inhibiting beta and gamma secretases that would normally increase b-amyloids. Vaccinate for b-amyloids, or look into cat's claw extracts.
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Which muscarinic agonists would you use to treat Alzheimer's disease?
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Xanomeline (but not made anymore), AF267B (good things in transgenic mice), CDD-0102 (new compound from UT)
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Which antioxidants would you use to treat Alzheimer's disease?
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Vitamins E & C, Resveritrol - an antioxidant in red wine
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What two major categories of cholinergic ligands are there?
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Nicotinic antagonists and nicotinic agonists.
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Almost all nicotinic antagonists result in what effect?
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Muscle paralysis in small muscles and then in larger ones. The depolarizing antagonists initially produce muscle fasciculations followed by their antagonizing effect.
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What are the three main classifications of nicotinic antagonists?
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Nicotinic antagonists are classified based on duration of action, chemical nature, and where they have their action.
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Which of the nicotinic antagonists are classified as long acting?
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D-Tubocurarine, metocurine, pancuronium
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Which of the nicotinic antagonists are classified as intermediate-length acting?
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Vecuronium, atracurium, and Rocuronium
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Which of the nicotinic antagonists are classified as short acting?
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Mivacurium
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Which of the nicotinic antagonists are classified as alkaloids?
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D-Tubocurarine, alcuronium
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Which of the nicotinic antagonists are classified as amino-steroids?
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Pancuronium, Pipecuronium, rocuronium
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Which of the nicotinic antagonists are classified as Benzylisoquinolines?
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Doxacurium, mivacurium
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Where are the two locations that nicotinic antagonists act best?
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At the neromuscular junction and at autonomic ganlia.
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What are the clinical uses of neuromuscular junction nicotinic receptor antagonists?
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They effectively block the contraction of skeletal muscle and are used in surgical anesthesia, in orthopoedic procedures, and in intubation.
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How are neuromuscular junction nicotinic receptor antagonists administered?
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Parenterally, usually IV, only by anesthesiologists within facilities fit for CV and respiratory resuscitation.
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What are some examples of neuromuscular junction nicotinic receptor antagonists?
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Snake venoms (a-bungarotoxin), curare derivatives (Tubocurarine), decamethonium, gallamine, and succinylcholine.
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What are the clinical uses of autonomic ganglia nicotinic receptor antagonists?
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Not many, limited to treatment of hypertension.
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Why do autonomic ganglia nicotinic receptor antagonists have a limited therapeutic use?
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Because their effects vary greatly and depend on the amount of sympathetic v. parasympathetic tone in any given organ.
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What effect do autonomic ganglia nicotinic receptor antagonists have on the CVS? What effect do they have on the eyes?
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They lead to vasodialation, decreased cariac output, hypotension, and tachycardia. They result in mydriasis (dialation).
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What are some examples of the autonomic ganglia nicotinic receptor antagonists?
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Trimethaphan, mecamylamine, and hexamethonium
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The three main categories of nicotinic agonists are?
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Analogs of nicotine, analogs of epibatadine, and other compounds.
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What are the nicotinic analogs potentially useful for?
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The treatment of Alzheimer's disease.
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The nicotinic agonists derived from epibatadine have what type of use?
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They function as cognitive enhancers (no duh...)
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Epibatidine itself was isolated from what? What was its original activity listed as?
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From the tree frog. Initially thought to have only analgesic effects.
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What does the 'other compounds' category of nicotinic agonists include?
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ABT-594 (developed for analgesia) and Altinicline (developed for Parkinson's disease)
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What effect do adrenergic agonists have on smooth muscle and glandular secretion?
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Excitatory, but inhibitory action on the smooth muscle of the GI tract and bronchi.
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What effect do adrenergic agonists have on the heart?
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They increase heart rate and force of contraction.
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What effect do adrenergic agonists have on metabolic activity?
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They increase glycogenolysis and the liberation of fatty acids from adipose tissue.
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What effect do adrenergic agonists have on the endocrine system?
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They will modulate hormones sucha s insulin, renin, and pituitary hormones.
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What effect do adrenergic agonists have on the CNS?
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They lead to respiratory stimulation, wakefulness, psychomotor activity, and appetite supression.
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What does "direct acting" adrenergic agonist mean, and provide some examples.
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Direct acting adrenergic agonists are agonists at a and b receptors. Some examples include norepinephrine, phenylephrine, and terbutaline.
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What does"indirect acting" adrenergic agonist mean.
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Indirect acting adrenergic agonists increase the release of norepinephrine, block its transport or block its metabolism.
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Provide some examples of indirect acting adrenergic agonists.
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amphetamines, cocaine, desipramine, pargyline, entacapone
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What does "mixed acting" adrenergic agonist mean?
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Mixed acting adrenergic agonists are agonists that increase catecholamine release and activate a and b receptors. An example includes ephedrine.
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In determining structure activity relationships, when starting with b-phenylethylamine and substituting on the a carbon, what occurs?
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The metbolism by MAO is blocked.
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In determining structure activity relationships, when starting with b-phenylethylamine and substituting on the b carbon, what occurs?
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Hydroxylation at the b carbon increases agonist activity but decreases CNS penetration.
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In determining structure activity relationships, when starting with b-phenylethylamine and substituting on the phenyl ring, what occurs?
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Hydroxylation results in a potent agonist, especially meta and para hydroxylation. This too, however, will decrease CNS penetration.
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In determining structure activity relationships, when starting with b-phenylethylamine and substituting alkyl groups at the nitrogen, what occurs?
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An increase in b receptor activity.
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Physiologically, what must we carefully consider in drug design of adrenergic agonists?
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The selectivity for a vs. b receptors. Since norepi. activates a receptors better, we see bronchial contraction, but since epi. activates b receptors better, we would see bronchial dialation.
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Explain how false transmitters can result in a depletion of norepinephrine?
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Some indirect acting amines can replace norepinephrine in the synaptic vessicles, and they are retained there due to their hydrophillic nature. This results in the depletion of norepinephrine.
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Explain how tyramine and MAO inhibitors may result in hypertensive crisis.
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MAO inhibitors block MAO which is normally responsible for metabolizing tyamine, a compound found in cheese, beer, and wine. Since this compound is not being metabolized, it remains in the bloodstream. Elevated tyramine results in massive norepi. dump.
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Which receptors does epinephrine activate?
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Both b and a adrenergic receptors.
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What effect does epinephrine have on blood pressure?
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It is a potent vasopressor, increasing cardiac forces, cardiac rate, and general casoconstriction.
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What vascular effects does epinephrine have?
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While epinephrine is a vasopressor, it directs blood flow to the skeletal muscle. This is done through b2 vasodialtion, more potent than a vasoconstriction.
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What effects does epinephrine have on cerebral blood flow?
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None
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What effects does epinephrine have on renal vascular resistance and renal blood flow?
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It increases renal vascular resistance and decreases renal blood flow. This effectively reserves sodium, potassium, and chloride.
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What cardiac effects does epinephrine have?
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It is a powerful cardiac stimulant through the b1-b3 receptors. We see an increase in heart rate, force of contraction and output, but a decrease in efficiency.
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What effects does epinephrine have on smooth muscle?
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It relaxes GIT, increases uterine contractions, but decreases them in the last month of pregnancy, and it relaxes the bladder detrussor muscle.
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What effects does epinephrine have on respiration?
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Relaxation of bronchial smooth muscle - bronchodialation.
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What effects does epinephrine have on the CNS?
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Limited brain access due to polar compound, but it results in apprehension, restlessness, headache, and tremor effects.
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What effects does epinephrine have on human metabolism?
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It elevates levels of glucose and lactose, it modulates insulin secretion predominately decreasing its release, increasing glycogenolysis, and it stimulates the release of free fatty acids by activating triglyceride lipase.
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How is epinephrine absorbed in the body?
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Not well through ingestion or subcutaneous, but very well I.M., I.V., or inhalation.
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How is epinephrine metabolized?
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It is rapidly inactivated by COMT and MAO.
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What toxicity does epinephrine result in?
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It results in restlessness, headache, tremor, palpitations, cardiac arrythmia, and cerebral hemorrhage.
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What are the therapeutic uses of epinephrine?
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Previously used to relieve respiratory distress of bronchospasem, but b-agonists are now preferred. Used to relieve hypersensitivity reactions, prolong local anesthetic actions, reverse cardiac arrest.
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Is norepinephrine a strong or weak b2 agonist?
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Weak
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What cardiovascular effects does norepinephrine have?
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It increases blood pressure, no cardiac changes, and general vasoconstriction.
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How is norepinephrine absorbed?
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Not orally or subcutaneously
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How is norepinephrine metabolized?
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Rapidly by MAO and COMT
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How is norepinephrine excreted?
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Its metabolites are excreted in the urine.
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What is there to note about toxicity associated with norepinephrine?
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Hypertension, necrosis and sloughing at IV site (reversible by phentolamine), Too little blood flow to kidney and liver is dangerous.
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How is norepinephrine therpeutically used?
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Used to treat shock, and low blood pressure.
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What effects does dopamine have in the CNS?
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It has effects tied with Parkinson's and schizophrenia.
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What effects does dopamine have in the kidney?
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It is a natriuretic, pumping out sodium and then allowing water to follow. Diuretic
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What effects does dopamine have in the CVS?
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It vasodialates, limits natiuresis, has a positive ionotropic effect on the heart, enhancing norepi. release and increasing blood pressure.
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What are some precautions to take with dopamine?
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There is a potential for excessive sympathomimetic activation.
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What are some adverse effects of dopamine?
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Nausea, vomiting, tachycardia, anginal pain, arryhthmias, headache, and hypertension.
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For which patients is dopamine contraindicated for?
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Those patients taking MAO inhibitors.
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What are the therpeutic uses of dopamine?
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Treating congestive heart failure, cardiogenic and septic shock, to regulate cardiac, brain, renal functions, and blood pressure.
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What are dopamine analogs being used for?
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Used for their vasodialating effects.
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What are b2 agonists useful for treating?
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Asthma by relaxing bronchial smooth muscle.
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Why would we administer b2 agonists by inhalation to asthmatics?
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To reduce other adverse effects associted with b2 receptor activation.
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What are some adverse effects attributed to excessive activation of b2 receptors?
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Tremor, tachycardia, arrhythmias, myocardial ischemia, MAO inhibitors, and potential link to death/near death by asthma due to down regulation (tolerance)
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What is Isoproterenol?
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A potent, non-selective b agonist
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What does Isoproterenol do to vascular resistance?
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It decreases vascular resistance but increases cardiac output
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How is Isoproterenol absorbed?
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Parenterally or aerosolized
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How is Isoproterenol metabolized?
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By COMT, not MAO
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What are some adverse effects of Isoproterenol?
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Palpitations, tachycardia, and headache
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What are some therapeutic uses of Isoproterenol?
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To stimulate heart rate in patients with bradycardia or heart block.
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What are some examples of b2 agonists?
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Metaproterenol, Terbutaline, Albuterol, Isoetharine, Pirbuterol, Bitolterol, Fenoterol, Formoterol, Procaterol, Salmeterol, Ritodrine
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What are the b2 agonists that have improved b2 selectivity and imrpoved oral bioavailability?
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Metaproterenol and terbutaline
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What do a1 agonists do?
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By activating receptors in vascular smooth muscle, they decrease vascular resistance and elevate blood pressure.
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How are a1 agonists used?
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They are used for treating hypotension or shock and as nasal decongestants
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What are some examples of a1 agonists?
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Phenylephrine, mephenteramine, metaraminol, midodrine
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What is Clonidine?
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An a2 agonist
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What is clonidine used for?
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Treatment of hypertension due to the activation of central a2 receptors, effectively decreasing the outflow of sympathetic nervous system activity from the brain.
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How is clonidine absorbed?
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Very well orally
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What is the half life of clonidine and how is it eliminated?
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Half life of 6-24 hrs., and 50% elimination via kidney.
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What are some adverse effects of clonidine?
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Drymouth and sedation.
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