Dementia Pharm, Sedative Hypnotics, Alcohol, Drugs of Abuse Flashcards
Central AChE inhibitor originally approved for dementia, but newer agents are now preferred due to high incidence of hepatotoxicity
Tacrine
Noncompetitive, reversible, centrally-acting AChE inhibitor approved for mild, moderate, or severe dementia of the Alzheimer type
Donepezil
3 AChE inhibitors approved for use in pts with dementia
Donepezil
Galantamine
Rivastigmine
Reversible AChE inhibitor utilized in mild, moderate, and severe dementia of Alzheimer type as well as mild to moderate dementia associated with Parkinson disease
Rivastigmine
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
Galantamine
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
Cholinergic; Parkinson
Signs of acute intoxication with AChE inhibitors like donepezil, rivastigmine, and galantamine
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
Treatment for acute AChE intoxication
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]
________, 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
Glutamate
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)
Memantine
Benzodiazepine with the fastest rate of onset after oral administration
Diazepam
[followed by alprazolam, flurazepam, chlorazepate > chlordiazepoxide, lorazepam, triazolam, clonazepam > oxazepam]
Slowest is oxazepam!
3 intermediate-to-long acting benzodiazepines
Diazepam
Lorazepam
Clonazepam
5 short-to-intermediate acting benzodiazepines
Alprazolam Oxazepam Temazepam Midazolam Triazolam
4 benzodiazepines with significant active metabolites
Chlordiazepoxide
Diazepam
Flurazepam
Chlorazepate
Newer sedative-hypnotic utilized for sleep maintenance
Zolpidem
Newer sedative-hypnotic good for pts who awaken early in sleep cycle
Zaleplon
______ and _____ are newer sedative-hypnotics that cause less amnesia and day-after somnolence than zolpidem or benzodiazepines
Eszopiclone; zaleplon
Newer sedative-hypnotic good for sleep-onset and maintenance; most common adverse effect is next-day somnolence
Suvorexant
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?
Flumazenil
MOA of flumazenil
Competitive antagonist at GABA-A receptor (same binding site as benzodiazepine)
MOA of benzodiazepines
Binds GABA-A receptor and enhances GABA’s effects
Increases Cl- influx, increased hyperpolarization, decreased number of APs (CNS depression)
MOA of barbiturates
Binds the GABA-A receptor; increases the duration of GABA-gated channel openings
Increases Cl- influx, increased hyperpolarization, decreased number of APs (CNS depression)
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
Buspirone
________ 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
Eszopiclone
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
Ramelteon
[MT1 agonism —> sleepiness; MT2 agonism —> regulation of circadian rhythms]
_______ 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
Zaleplon
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
Zolpidem
Sedative-hypnotic that affects the thalamus and limbic system; also appears to inhibit multineuronal spinal reflexes
Meprobamate
CNS depressant due to active metaboite trichloroethanol
Chloral hydrate
_____ 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
Hydroxyzine
Describe the relationships between dose of benzodiazepines and barbiturates and their CNS effects
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
Describe biotransformation pathway for benzodiazepines
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
4 drugs utilized in the treatment of acute alcohol withdrawal syndrome
Diazepam
Lorazepam
Oxazepam
Thiamine (B1)
3 drugs used for the prevention of alcohol abuse
Acamprosate
Disulfuram
Naltrexone
2 drugs utilized in the treatment of acute methanol or ethylene glycol poisoning
Ethanol
Fomepizol
What receptors are affected during acute ethanol exposure?
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]
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
Alcohol dehydrogenase (ADH); aldehyde dehydrogenase
Zero
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
Naltrexone
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
False!
Individuals physically dependent on alcohol and opioids must be OPIOID-FREE before initiating naltrexone therapy, because naltrexone precipitates an acute withdrawal syndrome
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)
Acamprosate
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
Disulfiram
T/F: When combined, alcohol, benzodiazepines, barbiturates, and sleep aids have additive effects on CNS depression
True
When consumed, methanol is converted by alcohol dehydrogenase and aldehyde dehydrogenase into toxic metabolites _________ and _______
When consumed, ethylene glycol is converted into toxic ______ and _______
Formaldehyde; formate
Aldehydes; oxalate
How is methanol toxicity treated?
Fomepizole
Ethanol
MOA of fomepizole in tx of methanol or ethylene glycol poisoning
Inhibits alcohol dehydrogenase —> reduction of toxic metabolite formation
Wernicke’s encephalopathy vs. Korsakoff’s psychosis (clinical features)
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
Appropriate drug therapy for Wernicke’s encaphalopathy
Benzodiazepines
Thiamine
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?
Mesolimbic
Dopamine
The dopamine hypothesis of addiction
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?
Opioids
Cannabinoids
y-Hydroxybutyric acid (GHB)
LSD
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?
Nicotine
Alcohol
Benzodiazepines
Phencyclidine
Ketamine
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?
Cocaine
Amphetamine
Ecstasy
General MOA of opioids as drugs of abuse
Agonists at mu-opioid receptor (Gi) —> disinhibition on dopamine neurons
Signs and symptoms of opioid intoxication
Pupil constriction
Decreased body temp
Decreased HR and BP
Sleepiness, droopy eyelids, soft low voice, euphoria
Signs/symptoms of opioid withdrawal
Dysphoria N/V/D Myalgias Lacrimation Rhinorrhea Mydriasis Piloerection Sweating Yawning Fever
Treatment options for opioid withdrawal
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
MOA of cannabinoids as drugs of abuse
Agonist at cannabinoid-1 (Gi) receptor —> disinhibition on dopamine neurons
Signs and symptoms of cannabinoid intoxication
Euphoria and relaxation, feelings of well-being, grandiosity, and altered perception of time passage, increased appetite
Signs/symptoms of cannabinoid withdrawal
Restlessness, irritability, mild agitation, insomnia, nausea, cramping
[mild and short-lived]
MOA of y-hydroxybutyric acid (GHB)
Weak agonist at GABA-B (Gi) receptors —> disinhibition on dopamine neurons
Signs and symptoms of intoxication with GHB
Before causing sedation and coma, causes euphoria, enhanced sensory perceptions, feeling of social closeness, and amnesia
MOA of LSD
Ergot alkaloid; partial agonist at 5-HT2A (Gq) receptor
Signs/symptoms of LSD intoxication
Induction of perceptual symptoms including shape and color distortion
Can induce abortion via stimulation of uterine contractions
MOA of nicotine as a drug of abuse
Agonist at nAChR —> excitation of dopamine neurons (direct stimulation)
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?
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
MOA of alcohol has a drug of abuse
Acts at GABA-A, 5-HT3, nAChR, NMDA, and Kir3 channels —> excitation, disinhibition on DA neurons
Signs and symptoms of alcohol withdrawal at 6-12 hours, 12-24 hours, 24-48 hours, and 48-72 hours after cessation
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
Treatment for alcohol withdrawal includes benzodiazepines that rely less on oxidative hepatic metabolism, such as ____ and _____
Oxazepam; lorazepam
Signs/symptoms of benzodiazepine withdrawal
Irritability, insomnia, phonophobia, photophobia, depression, muscle cramps, seizures
MOA of phencyclidine and ketamine as drugs of abubse
Antagonists at NMDA receptors
Signs/symptoms of intoxication with phencyclidine or ketamine
Unpleasant vivid dreams, hallucinations, psychedelic effects, increased BP, impaired memory function, visual alterations, out-of-body experiences
MOA of cocaine
Inhibitor at dopamine transporter (DAT), SERT, and NET —> blocks dopamine uptake
MOA of amphetamine
Reverses transport at DAT, NET, SERT, and vesicular monoamine transporter (VMAT) —> blocks DA uptake, synaptic depletion
MOA of ecstasy
Reverses transport at SERT > DAT, NET —> blocks DA uptake, synaptic depletion
______ is a BZD effective for status epilepticus and muscle spasticity. _________ is another BZD that is effective for status epilepticus
Diazepam; lorazepam
