Dementia Pharm, Sedative Hypnotics, Alcohol, Drugs of Abuse

Question 1

Central AChE inhibitor originally approved for dementia, but newer agents are now preferred due to high incidence of hepatotoxicity

Answer 1

Tacrine

Question 2

Noncompetitive, reversible, centrally-acting AChE inhibitor approved for mild, moderate, or severe dementia of the Alzheimer type

Answer 2

Donepezil

Question 3

3 AChE inhibitors approved for use in pts with dementia

Answer 3

Donepezil
Galantamine
Rivastigmine

Question 4

Reversible AChE inhibitor utilized in mild, moderate, and severe dementia of Alzheimer type as well as mild to moderate dementia associated with Parkinson disease

Answer 4

Rivastigmine

Question 5

Competitive, reversible centrally-acting AChE inhibitor that also modulates nAChR to increase from surviving presynaptic nerve terminals and may increase glutamate and serotonin levels; utilized in mild-to-moderate Alzheimers

Answer 5

Galantamine

Question 6

Pts with Alzheimer type progressive dementia have a deficiency of intact _____ neurons, which explains the utility of AChE inhibitors in the treatment of these pts. Pts with dementia associated with _____ disease also benefit

Answer 6

Cholinergic; Parkinson

Question 7

Signs of acute intoxication with AChE inhibitors like donepezil, rivastigmine, and galantamine

Answer 7

Signs of mAChR stimulation = miosis, salivation, sweating, bronchoconstriction, vomiting, diarrhea

With poisoning from lipid-soluble agents, CNS involvement follows rapidly — confusion, ataxia, generalized convulsions, coma, respiratory paralysis

Time of death after a single acute exposure may range 5 minutes to 24 hours and is caused primarily by respiratory failure

Question 8

Treatment for acute AChE intoxication

Answer 8

Atropine, pralidoxime, and a benzodiazepine are typically combined

[atropine acts at mAChRs, pralidoxime reactivates AChE by removing phosphorus group from active site, Benzodiazepine acts as an anticonvulsant]

Question 9

________, the primary excitatory amino acid in the CNS, may contribute to the pathogenesis of Alzheimer’s disease by overstimulating various receptors leading to excitotoxicity and neuronal cell death

Answer 9

Glutamate

Question 10

Antagonist of the NMDA type of glutamate receptor by binding to the intra-pore magnesium site with longer dwell-time, thus functioning as a receptor blocker only under conditions of excessive stimulation (does not affect normal neurotransmission)

Answer 10

Memantine

Question 11

Benzodiazepine with the fastest rate of onset after oral administration

Answer 11

Diazepam

[followed by alprazolam, flurazepam, chlorazepate > chlordiazepoxide, lorazepam, triazolam, clonazepam > oxazepam]

Slowest is oxazepam!

Question 12

3 intermediate-to-long acting benzodiazepines

Answer 12

Diazepam

Lorazepam

Clonazepam

Question 13

5 short-to-intermediate acting benzodiazepines

Answer 13

Alprazolam
Oxazepam
Temazepam
Midazolam
Triazolam

Question 14

4 benzodiazepines with significant active metabolites

Answer 14

Chlordiazepoxide
Diazepam
Flurazepam
Chlorazepate

Question 15

Newer sedative-hypnotic utilized for sleep maintenance

Answer 15

Zolpidem

Question 16

Newer sedative-hypnotic good for pts who awaken early in sleep cycle

Answer 16

Zaleplon

Question 17

______ and _____ are newer sedative-hypnotics that cause less amnesia and day-after somnolence than zolpidem or benzodiazepines

Answer 17

Eszopiclone; zaleplon

Question 18

Newer sedative-hypnotic good for sleep-onset and maintenance; most common adverse effect is next-day somnolence

Answer 18

Suvorexant

Question 19

Symptoms of benzodiazepine overdose are that of CNS depression — including disorientation, drowsiness, ataxia, slow slurred speech, etc. what agent is utilized to reverse benzodiazepine-induced sedation?

Answer 19

Flumazenil

Question 20

MOA of flumazenil

Answer 20

Competitive antagonist at GABA-A receptor (same binding site as benzodiazepine)

Question 21

MOA of benzodiazepines

Answer 21

Binds GABA-A receptor and enhances GABA’s effects

Increases Cl- influx, increased hyperpolarization, decreased number of APs (CNS depression)

Question 22

MOA of barbiturates

Answer 22

Binds the GABA-A receptor; increases the duration of GABA-gated channel openings

Increases Cl- influx, increased hyperpolarization, decreased number of APs (CNS depression)

Question 23

The MOA of ______ is unknown but it has a high affinity for 5-HT1A and 5-HT2 receptors and moderate affinity for D2 receptors, without affecting benzodiazepine GABA receptors

Answer 23

Buspirone

Question 24

________ is a highly effective, rapid onset sedative hypnotic with minimal hangover effects and a longer half life than zolpidem and zaleplon; may interact with GABA receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors

Answer 24

Eszopiclone

Question 25

Potent selective agonist of melatonin receptors MT1 and MT2 (with little affinity for M3) within suprachiasmatic nucleus of the hypothalamus, an area responsible for determination of circadian rhythms and synchronization of the sleep-wake cycle

Answer 25

Ramelteon [MT1 agonism —> sleepiness; MT2 agonism —> regulation of circadian rhythms]

Question 26

_______ is a newer sedative-hypnotic that interacts with the benzodiazepine GABA receptor complex; possibly at omega-1 recepto on alpha subunit of GABA-A receptor

Answer 26

Zaleplon

Question 27

Imidazopyridine hypnotic that enhances activity of GABA via selective agonism at benzodiazepine-1 receptor —> increased Cl conductance, neuronal hyperpolarization, inhibition of action potential, decrease in neuronal excitability

Answer 27

Zolpidem

Question 28

Sedative-hypnotic that affects the thalamus and limbic system; also appears to inhibit multineuronal spinal reflexes

Answer 28

Meprobamate

Question 29

CNS depressant due to active metaboite trichloroethanol

Answer 29

Chloral hydrate

Question 30

_____ competes with histamine for H1 receptor sites on effector cells in GI tract, blood vessels, and respiratory tract; has skeletal muscle relaxing, bronchodilator, antihistamine, antiemetic, and analgesic properties

Answer 30

Hydroxyzine

Question 31

Describe the relationships between dose of benzodiazepines and barbiturates and their CNS effects

Answer 31

Most sedative-hypnotics exhibit graded dose-dependent depression of CNS function Older sedative-hypnotics like barbiturates and alcohols: increase in dose higher than that needed for hypnosis may lead to state of general anesthesia —> higher doses lead to respiratory and vasomotor center depression in medulla leading to coma and death Benzodiazepines and newer sedative-hypnotics: require proportionately greater dosage increments to achieve CNS depression more profound than hypnosis

Question 32

Describe biotransformation pathway for benzodiazepines

Answer 32

Hepatic metabolism; mostly via phase I reactions via CYP450 enzymes (esp CYP3A4), then phase II reactions to form glucuronides that are excreted in urine Many phase I metabolites of benzodiazepines are pharmacologically active — those metabolites with long half lives are more likely to cause cumulative effects with multiple doses

Question 33

4 drugs utilized in the treatment of acute alcohol withdrawal syndrome

Answer 33

Diazepam Lorazepam Oxazepam Thiamine (B1)

Question 34

3 drugs used for the prevention of alcohol abuse

Answer 34

Acamprosate Disulfuram Naltrexone

Question 35

2 drugs utilized in the treatment of acute methanol or ethylene glycol poisoning

Answer 35

Ethanol | Fomepizol

Question 36

What receptors are affected during acute ethanol exposure?

Answer 36

Acute ethanol exposure enhances the action of GABA and GABA-A receptors Ethanol also inhibits the ability of glutamate to open NMDA-subtype of glutamate receptors [the NMDA receptor is implicated in aspects of cognitive function including learning/memory]

Question 37

The overall metabolism of ethanol involves extensive first pass metabolism by gastric and liver enzyme __________________, followed by ________________. Metabolism follows ____-order kinetics in that the rate of biotransformation is independent of time and concentration of ethanol; enzymes are almost immediately saturated

Answer 37

Alcohol dehydrogenase (ADH); aldehyde dehydrogenase Zero

Question 38

Drug used in the setting of alcohol cravings that acts as a mu-opioid receptor antagonist (long-acting), and reduces craving for alcohol and rate of relapse to either drinking or alcohol dependence in the short-term

Answer 38

Naltrexone

Question 39

T/F: individuals physically dependent on alcohol and opioids should not stop their opioid use prior to initiating therapy with naltrexone in order to avoid an acute withdrawal syndrome

Answer 39

False! Individuals physically dependent on alcohol and opioids must be OPIOID-FREE before initiating naltrexone therapy, because naltrexone precipitates an acute withdrawal syndrome

Question 40

Drug used in the setting of alcohol cravings that acts as a weak NMDA receptor antagonist and GABA-A receptor agonist (also affects serotonergic, noradrenergic, and dopaminergic systems) Reduces short-term and long-term relapse rates (more than 6 mos)

Answer 40

Acamprosate

Question 41

Drug used in the setting of alcohol cravings that irreversibly inhibits aldehyde dehydrogenase —> accumulation of aldehyde; causes extreme discomfort in pts who drink alcohol — flushing, headache, N/V, sweating

Answer 41

Disulfiram

Question 42

T/F: When combined, alcohol, benzodiazepines, barbiturates, and sleep aids have additive effects on CNS depression

Answer 42

True

Question 43

When consumed, methanol is converted by alcohol dehydrogenase and aldehyde dehydrogenase into toxic metabolites _________ and _______ When consumed, ethylene glycol is converted into toxic ______ and _______

Answer 43

Formaldehyde; formate Aldehydes; oxalate

Question 44

How is methanol toxicity treated?

Answer 44

Fomepizole | Ethanol

Question 45

MOA of fomepizole in tx of methanol or ethylene glycol poisoning

Answer 45

Inhibits alcohol dehydrogenase —> reduction of toxic metabolite formation

Question 46

Wernicke’s encephalopathy vs. Korsakoff’s psychosis (clinical features)

Answer 46

Wernicke’s encephalopathy — paralysis of the external eye muscles, ataxia, and confusion; can progress to coma and death Korsakoff’s psychosis — chronic disabling memory disorder following Wernicke’s encephalopathy

Question 47

Appropriate drug therapy for Wernicke’s encaphalopathy

Answer 47

Benzodiazepines | Thiamine

Question 48

As a general rule, all addictive drugs activate the ______ dopamine system. Dopamine within this system codes for the difference between expected and actual reward, thus constituting a strong learning signal. This system continuously scans for reward, increasing its activity when reward is larger than expected, and shutting down when reward does not occur. By directly increasing ________, addictive drugs generate a strong but inappropriate learning signal, thus hijacking the reward system and leading to pathologic reinforcement. *What hypothesis does this describe?*

Answer 48

Mesolimbic Dopamine The dopamine hypothesis of addiction

Question 49

Drugs of abuse can be placed into 3 categories: Drugs that activate GPCRs, Drugs that bind ionotropic receptors and ion channels, and Drugs that bind to transporters of biogenic amines. What are 4 drugs of abuse that activate GPCRs?

Answer 49

Opioids Cannabinoids y-Hydroxybutyric acid (GHB) LSD

Question 50

Drugs of abuse can be placed into 3 categories: Drugs that activate GPCRs, Drugs that bind ionotropic receptors and ion channels, and Drugs that bind to transporters of biogenic amines. What are 5 drugs of abuse that bind ionotropic receptors and ion channels?

Answer 50

Nicotine Alcohol Benzodiazepines Phencyclidine Ketamine

Question 51

Drugs of abuse can be placed into 3 categories: Drugs that activate GPCRs, Drugs that bind ionotropic receptors and ion channels, and Drugs that bind to transporters of biogenic amines. What are 3 drugs of abuse that bind transporters of biogenic amines?

Answer 51

Cocaine Amphetamine Ecstasy

Question 52

General MOA of opioids as drugs of abuse

Answer 52

Agonists at mu-opioid receptor (Gi) —> disinhibition on dopamine neurons

Question 53

Signs and symptoms of opioid intoxication

Answer 53

Pupil constriction Decreased body temp Decreased HR and BP Sleepiness, droopy eyelids, soft low voice, euphoria

Question 54

Signs/symptoms of opioid withdrawal

Answer 54

``` Dysphoria N/V/D Myalgias Lacrimation Rhinorrhea Mydriasis Piloerection Sweating Yawning Fever ```

Question 55

Treatment options for opioid withdrawal

Answer 55

Naloxone — reverses effects of morphine or heroin in minutes; provokes an acute withdrawal syndrome in a dependent pt who has recently taken an opioid Methadone, buprenorphine, morphine sulfate — longer acting opioids that act as substitution therapy

Question 56

MOA of cannabinoids as drugs of abuse

Answer 56

Agonist at cannabinoid-1 (Gi) receptor —> disinhibition on dopamine neurons

Question 57

Signs and symptoms of cannabinoid intoxication

Answer 57

Euphoria and relaxation, feelings of well-being, grandiosity, and altered perception of time passage, increased appetite

Question 58

Signs/symptoms of cannabinoid withdrawal

Answer 58

Restlessness, irritability, mild agitation, insomnia, nausea, cramping [mild and short-lived]

Question 59

MOA of y-hydroxybutyric acid (GHB)

Answer 59

Weak agonist at GABA-B (Gi) receptors —> disinhibition on dopamine neurons

Question 60

Signs and symptoms of intoxication with GHB

Answer 60

Before causing sedation and coma, causes euphoria, enhanced sensory perceptions, feeling of social closeness, and amnesia

Question 61

MOA of LSD

Answer 61

Ergot alkaloid; partial agonist at 5-HT2A (Gq) receptor

Question 62

Signs/symptoms of LSD intoxication

Answer 62

Induction of perceptual symptoms including shape and color distortion Can induce abortion via stimulation of uterine contractions

Question 63

MOA of nicotine as a drug of abuse

Answer 63

Agonist at nAChR —> excitation of dopamine neurons (direct stimulation)

Question 64

Signs and symptoms of nicotine intoxication —> increased pulses and BP, odor on breath, stained fingers or teeth. Signs/symptoms of withdrawal may include irritability and sleep problems. How is nicotine withdrawal treated?

Answer 64

Nicotine given in slowly absorbing forms — gum, inhaled, transdermal Varenicline, plant-extract cytisine — occupy nAChRs on dopamine neurons of VTA, preventing nicotine from exerting its action Buproprion — weak inhibitor of neuronal uptake of NE and DA

Question 65

MOA of alcohol has a drug of abuse

Answer 65

Acts at GABA-A, 5-HT3, nAChR, NMDA, and Kir3 channels —> excitation, disinhibition on DA neurons

Question 66

Signs and symptoms of alcohol withdrawal at 6-12 hours, 12-24 hours, 24-48 hours, and 48-72 hours after cessation

Answer 66

6-12 hrs — tremor, N/V, excess sweating, agitation, anxiety 12-24 hrs — visual, tactile, auditory hallucinations 24-48 hrs — generalized seizures 48-72 hrs — alcohol withdrawal delirium (delirium tremens): hallucinations, disorientation, autonomic instability; 5-15% mortality

Question 67

Treatment for alcohol withdrawal includes benzodiazepines that rely less on oxidative hepatic metabolism, such as ____ and _____

Answer 67

Oxazepam; lorazepam

Question 68

Signs/symptoms of benzodiazepine withdrawal

Answer 68

Irritability, insomnia, phonophobia, photophobia, depression, muscle cramps, seizures

Question 69

MOA of phencyclidine and ketamine as drugs of abubse

Answer 69

Antagonists at NMDA receptors

Question 70

Signs/symptoms of intoxication with phencyclidine or ketamine

Answer 70

Unpleasant vivid dreams, hallucinations, psychedelic effects, increased BP, impaired memory function, visual alterations, out-of-body experiences

Question 71

MOA of cocaine

Answer 71

Inhibitor at dopamine transporter (DAT), SERT, and NET —> blocks dopamine uptake

Question 72

MOA of amphetamine

Answer 72

Reverses transport at DAT, NET, SERT, and vesicular monoamine transporter (VMAT) —> blocks DA uptake, synaptic depletion

Question 73

MOA of ecstasy

Answer 73

Reverses transport at SERT > DAT, NET —> blocks DA uptake, synaptic depletion

Question 74

______ is a BZD effective for status epilepticus and muscle spasticity. _________ is another BZD that is effective for status epilepticus

Answer 74

Diazepam; lorazepam