unit 9 Flashcards

Question

tolerance of barbituates

Answer 1

tolerance develops to the sedative-hypnotic effects of barbiturates *metabolic tolerance – enzyme induction *pharmacodynamic tolerance – adaptation of nervous tissue to drug presence

Answer 2

*large problem!! *withdrawal symptoms may be severe (e.g., seizures)

Answer 3

*moderate intoxication similar to alcoholic inebriation *symptoms of severe intoxication: coma – can last up to five days with phenobarbital; constricted pupils  dilation due to hypoxia; breathing slow or rapid and shallow; shock syndrome may develop (fall in blood pressure) *death may be due to respiratory depression or complications of prolonged coma (pulmonary edema) *treatment – charcoal lavage; intensive support therapy (respiratory); no stimulants; hemodialysis

Answer 4

uses boil down to some basic pharmacokinetics: their lipid solubility. The higher the lipid solubility, the quicker the onset of action and shorter the duration of effect. Thiopental is used to help you relax before you receive general anesthesia with an inhaled medication. It was once thought to be “truth serum”. Secobarbital and Pentobarbital are used short-term to treat insomnia, an emergency treatment for seizures, or as a sedative before surgery. Phenobarbital is a treatment of certain types of epilepsy in developing countries and commonly used to treat seizures in young children. Secobarbital, Pentobarbital and Phenobarbital used in the US for physician-assisted suicide and executions of criminals.

Answer 5

Metabolic tolerance is an issue with barbiturates. With repeated use there is substantial increase in liver microsomal enzymes which increases drug metabolism and thus requiring more drug to give the desired effect. Note here that, while more drug is required to get the desired effect, the dose for respiratory depression does not change! Thus, the therapeutic index and margin of safety shrinks. The above are theoretical dose-response curves for the barbiturate-induced desired effect (e.g., mood change or sedation) and lethal respiratory depression. The top panel shows that with early drug use (non-tolerant) the individual experiences mood effects without significant respiratory depression. However, as tolerance develops with repeated use (bottom panel), larger amounts of drug are needed to experience the mood change (the curve shifts to the right) but no change in the dose causing depression of respiration occurs. The margin of safety (i.e., therapeutic index) shrinks dramatically in the tolerant individual.

Answer 6

Another problem with barbiturates is that they promote sleep, but not normal, restful sleep. They disrupt typical sleep architecture. Recall that sleep stages are cycled-through about 4-5 times per night with several bouts of REM sleep. The left panel shows the initial effects of pentobarbital, which include a short onset of sleep and few spontaneous awakenings. The right panel shows the changes after chronic nightly use of the drug. Tolerance is shown by the long onset of sleep (1 hour) and the 12 spontaneously awakenings during the night. Both REM and stages 3 and 4 sleep are suppressed

Answer 7

Effect of barbiturate on mothers in labor. Blood levels of secobarbital in mothers and their newborn infants after intravenous administration of the drug to the mothers. Each point represents one subject (circles, mothers; asterisks, infants).

Answer 8

*today, the most commonly used sedative - hypnotics

Answer 9

*preferentially act on the limbic system (septum, amygdala and hippocampus) where they potentiate GABAergic inhibitory neurotransmission *increases the frequency of GABA-Cl channel opening

Answer 10

* benzodiazepines are weakly basic (therefore absorbed better in duodenum) * several are metabolized to active forms - the more lipophilic benzodiazepines have shorter onset and duration of action

Answer 11

*safer, higher therapeutic index *less depression of respiration *less induction of hepatic drug-metabolizing enzymes *slower development of tolerance *lower risk of physical dependence, withdrawal symptoms not severe *less depression of REM sleep

Answer 12

1. Chlordiazepoxide * Anticonvulsant, muscle relaxing properties, sedative and hypnotic effects. Used primarily in anxiety and muscular-skeletal disorders, and alcohol withdrawal syndromes; premedical treatment to anesthesia. * is used for treatment of prolonged anxiety, because of its long duration of action * is similar to meprobamate and barbiturates in general; cumulative effect and the withdrawal symptoms 2. Diazepam * an anticonvulsant and treatment of status epilepticus * used as an amnesic agent in dental surgery and for possible amnesic effects in procedures such as endoscopy and bronchoscopy * useful in acute alcohol withdrawal 3. Oxazepam * is an metabolite of diazepam with short duration of action

Answer 13

*tolerance, physical dependence and cross tolerance occur with benzodiazepines and ALL other sedative-hypnotics including ethanol *tolerance is common. and overdoses are frequent. However, serious consequences are rare. Treatment includes support of respiration and cardiovascular functions.

Answer 14

Long-acting benzodiazepines undergo several metabolic changes (phase 1) that create active metabolites(A) before being conjugated (phase II) with glucuronide to form a water-soluble inactive metabolite for excretion. (UDP= uridine diphosphate) Not important to know the name of the conjugate or the product excreted.

Answer 15

non-barbiturates/non-benzodiazepine * chemically reduced to the active metabolite in liver * the same sedative-hypnotic properties as barbiturates * currently used as pre-medication for children and elderly

Answer 16

non-barbiturates/non-benzodiazepine *possess sedative-hypnotic, anticonvulsant and muscle relaxing properties; used primarily in anxiety and muscular-skeletal disorders (e.g., muscle spasm); of no value in treating psychoses; suppresses REM sleep *ability to produce habituation and physical dependence similar to that for barbiturates; toxicity includes sleepiness, ataxia, hypotension; and massive overdose results in coma, shock, pulmonary edema and respiratory depression. The dose necessary to produce profound CNS depression is usually considered to be very much greater than that of a barbiturate. *the drug should be withdrawn gradually and slowly *the locus and mechanism of action are unknown

Answer 17

*it is an effective anti-anxiety drug and is a 5-HT1A receptor agonist *has no effect on GABA or benzodiazepine binding *has little interaction with CNS depressants, but caution must be exercised with alcohol *possesses no anticonvulsant properties *has lower risk of dependence *has no effect on panic disorder *elicits no cross tolerance with other anti-anxiety drugs

Answer 18

After administration of ethanol (2 g/kg i.p.) to mice, the brain ethanol concentration reached its peak in about 15 min, and did not equate with ethanol levels in venous blood taken from the tip of the tail until 60 min had passed. - the alcohol molecule is both hydrophilic and lipophilic

Answer 19

After three doses of alcohol (1.0 g/kg at time a, and 0.25 g/kg at times b and c), signs of intoxication appeared during the rising phase of the blood alcohol concentration (BAC) curve when the BAC was about 200 mg/dl. However, when the BAC was declining, the subject became sober even though the BAC was about 265 mg/dl. - tolerance is quicker

Answer 20

Alcohol also inhibits glutamate, particularly at the N-methyl-d-aspartate (NMDA) glutamate receptor. It does this by two means. First, it inhibits NMDA receptors so that the channels do not fully open so that there is less entry of sodium (Na+) and calcium (Ca2+) into the cell for less excitation. Secondly, alcohol may also increase activity of presynaptic metabotropic glutamate receptors to decrease glutamate release. Therefore, alcohol has two ways to inhibit the main “excitatory” transmitter in the brain.

Answer 21

receptor antagonism and reduced glutamate release

Answer 22

memory loss, rebound hyperexcitability of the abstinence syndrome

Answer 23

increase in GABA-induced CL= influx to hyperpolarize

Answer 24

sedative effects, anxiety reduction, sedation, incoordination, memory impairment, tolerance and signs of hyperexcitability during withdrawal

Answer 25

increase in dopamine transmission in mesolimbic tract

Answer 26

reinforcement, negative affect as a sign of withdrawal

Answer 27

increase in endogenous opioid synthesis and release

Answer 28

neuroadaptive decrease in endorphin levels

Answer 29

reinforcement and dysphoria

Answer 30

can have anxiogenic effects or even convulsive effects

Answer 31

Ethanol is oxidated by the enzyme alcohol dehydrogenase using NAD+ as a cofactor to form acetaldehyde. A second oxidative step converts acetaldehyde to acetic acid, which, in turn, is broken down to carbon dioxide and water. The first step involving alcohol dehydrogenase is the rate-limiting step. The drug disulfiram (Antabuse) blocks the second step by blocking the activity of aldehyde dehydrogenase. This is important to know this two step process.

Answer 32

the enzyme alcohol dehydrogenase using NAD+ as a cofactor to form acetaldehyde. A second oxidative step converts acetaldehyde to acetic acid, which, in turn, is broken down to carbon dioxide and water. The first step involving alcohol dehydrogenase is the rate-limiting step. The drug disulfiram (Antabuse) blocks the second step by blocking the activity of aldehyde dehydrogenase.

Answer 33

Ethanol is oxidated by the enzyme alcohol dehydrogenase using NAD+ as a cofactor to form acetaldehyde. A second oxidative step converts acetaldehyde to acetic acid, which, in turn, is broken down to carbon dioxide and water. The first step involving alcohol dehydrogenase is the rate-limiting step. The drug disulfiram (Antabuse) blocks the second step by blocking the activity of aldehyde dehydrogenase.

Answer 34

- when used alone, either alcohol or narcotic drugs cause a reduction in the function of the central nervous system. when they are used together is effect is even greater and may lead to loss of effective breathing function (respiratory arrest) death may occur

Answer 35

1. Intellectual disability and developmental delays 2. Low birthweight 3. Neurological disorders (tremor, irritability auditory hypersensitivity, etc.) 4. Craniofacial malformations 5. Assorted physical abnormalities

Answer 36

In U.S. nearly 75% of adults drink ETOH. 15% of ETOH users in the U.S. are considered to have a drinking problem or are subject to alcoholism. 10 million Americans are classified as alcoholics. Alcoholism is most severe of all substance abuse in USA. More people become dependent on ETOH, become psychotic through excessive use of it and are killed or disabled by it than by all other abused drugs (except nicotine via tobacco) put together. 11 million accidents each year are ETOH-related. Alcohol Abuse Disorder costs the U.S. economy $136 billion.

Answer 37

an illness characterized by preoccupation with alcohol and loss of control over its consumption such as to lead usually to intoxication if drinking is begun; the condition is chronic, progressive, and has a tendency toward relapse. It is typically associated with physical disability and impaired emotional, occupational, and/or social adjustments as a direct consequence of persistent and excessive use of alcohol.

Answer 38

Biological, psychological, and sociocultural influences contribute to the development of alcohol abuse.

Answer 39

Epilepsy affects about 0.5% of the population. The characteristic event is the seizure, which is often associated with convulsions, but may occur in many other forms. The seizure is caused by an abnormal high frequency discharge of a group of neurons, starting locally and spreading to a varying extent to affect other parts of the brain. Seizures may be partial or generalized depending on the location and spread of the abnormal neuronal discharge. The attack may involve mainly motor, sensory or behavioral phenomena. Unconsciousness occurs when the reticular formation is involved. Partial seizures are often associated with damage to the brain, whereas generalized seizures occur without obvious cause. Two common forms of generalized epilepsy are the tonic-clonic fit (grand mal) and the absence seizure (petit mal). The neurochemical basis of the abnormal discharge is not well understood. It may be associated with enhanced excitatory amino acid transmission, impaired inhibitory transmission, or abnormal electrical properties of the affected cells. Prolonged epileptic discharge (status epilepticus) can cause neuronal death (excitotoxicity). Current drug therapy is effective in 70-80% of epileptic patients.

Answer 40

generalized seizures, i.e. they spread through or affect the entire brain. A patient experiencing a grand mal seizure may experience an aura before the seizure begins. The person experiencing a grand mal seizure collapses, loses consciousness and goes into convulsions. The patient is often unconscious after the seizure's end. During a petit mal seizure, the patient loses consciousness for 10 to 15 seconds and then makes a complete recovery, while a person having an “absence seizure” may suddenly stop and stare into space. Someone witnessing such a seizure may think the person has simply stopped paying attention or is daydreaming. After the seizure is over, the sufferer has no memory of it. The patient has no need for medical attention or special care during or after the seizure.

Answer 41

With Tonic-Clonic Seizures, the tonic phase is typically short duration (a few second) during which the subject tenses and may lose consciousness. Then, during the clonic phase, the subject will shake uncontrollably. The main point here is the the neural excitability—the high-frequency firing of the neuron. A paroxysmal depolarizing shift (PDS) or depolarizing shift is a cellular manifestation of epilepsy. First, there is a Ca mediated depolarization, which causes voltage gated Na to open, resulting in action potentials. This depolarization is followed by a period of hyper-polarization mediated by Ca-dependent K channels or GABA-activated Cl influx. The extracellular recording was made through a high-pass filter. Note the high-frequency firing of the neuron evident in both extracellular and intracellular recording during the paroxysmal depolarization shift (

Answer 42

phenytoin, carbamazepine, valproate

Answer 43

phenobarbital, clonzepam, vigabatrin, tiagabine, gabapentin

Answer 44

ethosuximide

Answer 45

enhance Na+ channel inactivation, enhance GABAergic transmission, inhibit Ca2+ channels - Note that a commonality of antiseizure drugs is to inhibit depolarization of cells, or increase polarization, by acting on ionic receptors. Thus drugs such as carbamazepine and valproate inactivate sodium channels so less positive charge enters the cell. Phenobarbital and clonazepam stimulate the GABA receptor. Ethosuximide inhibits Calcium channels.

Answer 46

Carbamazepine and Valproate are antiseizure drugs (shown in blue text) that prolong the inactivation of the Na+ channels, thereby reducing the ability of neurons to fire at high frequencies. Note that the inactivated channel itself appears to remain open but is blocked by the inactivation gate (I). A, activation gate.

Answer 47

stimulates production of GABA, and inhibits breakdown of the chemical. In the presence of GABA, the GABAA receptor allows an influx of Cl-, which in turn increases membrane polarization. Some antiseizure drugs act by reducing the metabolism of GABA. Others act at the GABAA receptor, enhancing Cl- influx. GABA-T, GABA transaminase; GAT-1, GABA transporter.

Answer 48

is following an influx of Cl-, which in turn increases membrane polarization. Some antiseizure drugs act by reducing the metabolism of GABA. Others act at the GABAA receptor, enhancing Cl- influx. Gabapentin acts presynaptically to promote GABA release; its molecular target is currently under investigation. GABA-T, GABA transaminase; GAT-1, GABA transporter.

Answer 49

insomnia therapy - intermediate half-life - some daytime sedation and performance decrements

Answer 50

insomnia therapy - long half life advantage = delayed rebound insomnia disadvantage = daytime sedation - high risk of falls and driving errors

Answer 51

insomnia therapy - intermediate half-life - some daytime sedation and performance decrements

Answer 52

insomnia therapy - short half-life - no day-time sedation disadvantage = rebound insomnia

Answer 53

insomnia therapy - short half-life - no daytime sedation disadvantage = rebound insomnia

Answer 54

estazolam, flurazepam, temazepam, triazolam, zolpidem

Answer 55

antidepressants (amitriptyline, doxepin, trazodone) antipsychotics (haloperidol, chlorpromazine) barbiturates antihistamines (diphenhydramine)

Answer 56

and insomnia is a symptom of most mental illnesses. This type of insomnia is properly secondary insomnia – the cause is the mental illness and the insomnia will be relieved if the underlying illness is cleared up.

Answer 57

have been linked for some time and most sleep specialists believe that insomnia is often a secondary symptom to clinical depression. A number of anti-depressant drugs are notable for applications as sleep aids. Trazodone is one of the most popular.

Answer 58

are medications commonly used to treat schizophrenia and sometimes acute psychosis.

Answer 59

can make you feel drowsy, and therefore help you get to sleep for two to three nights — but regular use can make insomnia worse. Diphenhydramine is sold as Benadryl.

Answer 60

advantages in insomnia therapy = no tolerance, few anticholinergic effects disadvantages = extrapyramidal effects; increased risk of falls; limited sedation

Answer 61

advantages in insomnia therapy = no tolerance disadvantages = extrapyramidal effects, increased risk of falls, anticholinergic delirium