Sedatives and Stimulants PDF

Sedative/Hypnotics Definition: Sedative (anxiolytic) exert a calming effect Therapeutic goal not more Hypnotic: drowsiness-encourage sleep. Sedation---hypnosis (not state of suggestibility) Clinical uses: Relief of anxiety Insomnia...

Sedative/Hypnotics Definition: Sedative (anxiolytic) exert a calming effect Therapeutic goal not more Hypnotic: drowsiness-encourage sleep. Sedation---hypnosis (not state of suggestibility) Clinical uses: Relief of anxiety Insomnia Sedation/amnesia prior to or during medical/dental treatments Epilepsy/seizure Control of withdrawal—ethanol, other sedatives Muscle relaxation https://www.youtube.com/watch?v= bEcdGK4DQSg Anxiety Similar to fear: prepared for danger… Acute (normal) or pathological (maladaptive) Can be chronic displays a wide range of symptoms and is variable with major life disruptions Processing of threats is normal but with anxiety our attention is drawn to cues linked to the object or events that we are concerned with. Amygdala (threat processing) > PFC (executive function) Real stressors vs imagined stessors When the stress response is on all the time we have problems Diabetes, heart disease, dna aging etc. Bad gene Primates are smart enough…Sapolsky symptom Fear of flying good gene environment Developmental disorder with onset as early as 11 years. Associated with Stress during critical developmental periods interacting with genetic vulnerabilities  Anxiety Most prevalent psychiatric disorder in the US ~20% Often occurs with other illnesses e.g. substance abuse or major depression Depression plus Anxiety correlated to traumatic/stressful event during development. Depression alone does not.  Anxiety Panic disorder: Agoraphobia: Post-Traumatic stress disorder (PTSD): Generalized anxiety disorder (GAD): Social anxiety disorder (SAD): Obsessive compulsive disorder (OCD): Simple Phobias Disabling fear which effects behavior, motor and autonomic function and sleep  Agents used in anxiety Acute anxiety: benzodiazepines (can be used longer for Panic disorder) (Barbs historical) SSRIs, SNRIs: take time to have benefit so useful for long term control Atypical Antipsychotics: Quetiapine (Seroquel), Ziprasidone (Geodon) adjuncts. Antiepileptics: gabapentin, pregabalin  Agents used for hypnosis Benzos and Z-drugs Barbs?? Ramelteon Orexin antag. Sedating Anti depressants  Sedative/Hypnotics Benzodiazepines and Barbiturates Differ in degree of CNS depression They have similar mechanisms but very different safety profiles.  Sedative/Hypnotics Barbs Respiratory/cardiovascular depression--coma Anesthesia BZDs CNS Effect Sedation Anticonvulsant Anxiolytic Dose Dose/response curve of two major classes of sedative/hypnotic agents  Sedative/Hypnotics Barbits. Drowsiness—sleep—coma and death. BZDs—much safer Calm—sedation-sleep—not fatal resp. depression (one possible exception midazolam) With other CNS depressants can kill.  Drugs used by M. Jackson at time of death. Being treated for insomnia: Valium Xanax Versed Propofol Opioids etc. found on premises What did the Physician administer when he found him unresponsive?  BZD and Barb MOA Benzos, Non-benzos, Barbs act by potentiating inhibitory neurotransmission in the CNS. They enhance the actions of Gamma- aminobutyric acid (GABA) at the GABA-A receptor subtype. Allosteric potentiation (PAMs)  Distinct GABA receptor binding sites Pentameric Benzodiazepine ligand gated Binding site ion channel Barbiturate Binding site  MOA BZDs and Barbs P.A.Ms. Benzodiazepines: Increase the frequency of channel openings in the presence of GABA Barbiturates Increase mean open time of channels in presence of GABA Direct opening, no GABA, dangerous resp fail Mechanisms of Action  Characteristics Pharmacological properties of agents differ: potency onset (lipophilicity) duration of action (active metabolites) Contributes to side effect profiles Like rebound insomnia or next day drowsiness Consequently the best uses Uses: Anxiolytics, hypnotics, antiepileptics, muscle relaxation, anesthesia, alcohol withdrawal Vary in rate of onset, duration and side effects; Oral, IM, IV, rectal Agents Uses Duration Diazepam (Valium) Anxiety, status epilepticus, anesthesia, Long 1-3 days withdrawal, muscle spasms Alprazolam (Xanax) Anxiety disorders, agoraphobia Medium 10-20 hrs Chlordiazepoxide Anxiety disorders, alcohol withdrawal Long 1-3 days (Librium) Lorazepam (Ativan) Anxiety disorders, seizures Medium 10-20 hrs (Directly conjugated) Triazolam (Halcion) Insomnia Short 3-8 hrs Clonazepam (Klonopin) Prophylactic anti-convulsant (petit mal) Long 1-3 days panic disorder, RLS (off label) Midazolam (Versed) Preanesthesia, sedation, conscious Short 3-8 hrs sedation w/ fentanyl  Pharmacokinetics Distribution Orally: Rapidly absorbed—widely distributed (ex clorazepate converted in GI before) IM poor absorption Low solubility not many I.V. valium, Ativan and versed All cross BBB and placental barrier and in breast milk (can lead to depression of neonatal vitals) Hepatic metabolism for all BZDs Cyp3A4 and Cyp2C19 Inhibited by: Erythromycin, ritonavir, ketoconazole, grapefruit juice among others. Many have active metabolites  Biotransformation Chlordiazepoxide Diazepam Clorazepate (inactive) Desmethylchlordiazepoxide Desmethyldiazepam Demoxepam Alprazolam and Oxazepam Triazolam α-hydroxy metabolites* Diazepam (Valium) has two active metabolites- Conjugation Lorazepam desmethyldiazepam and oxazepam 1-2 days to 2-5 days Urinary excretion contributes to daytime sedation  So the Pharmacological properties: onset potency duration of action Determines the best use and side effect profiles:  Therapeutic uses Anxiolytics, hypnotics, antiepileptics, muscle relaxants, anesthesia and ease etoh withdrawal Interchangeable but indications depend on pharmacological properties Antiepileptics: long ½ life and rapid onset Diazepam (Valium), Clonazepam (Klonopin) Hypnotics: short ½ life rapid onset Triazolam (Halcion) (daytime anxiety due to withdrawal) Anxiolytics: long ½ life Alprazolam (Xanax) Panic and GAD, clonazepam (Klonopin) GAD social, Lorazepam (Ativan) Panic disorder Withdrawal symptoms: long ½ Chlordiazepoxide (Librium) + Diazepam (Valium)  Adverse effects High safety margin, however: !!Prolonged use can lead to dependence and tolerance!!! Only prescribe for short periods (can develop w/in 7 days) Tolerance: uninhibitedness, euphoria + antiep and muscle relax (little to anxiolytic or amnesic) Receptor down-regulation Cross tolerance – ethanol and other BZD  Adverse effects Dependence: severe withdrawal syndrome anxiety, insomnia, muscle/joint pain, convulsions, psychosis, heart prob, coma, suicide, death Severity: dose and elimination High dose with few active metabolites worse Triazolam for insomnia Low dose with many active metabolites so withdrawal less severe with diazepam than alprazolam This mimics tapering of drug Drugs of abuse: Prescription only short term and TAPER to remove! With other CNS depressants can be fatal  Non-Benzodiazepine (Z-Drugs) Zolpidem BZD Zaleplon Zolpidem (Ambien), Zaleplon (Sonata), Es-Zopiclone (Lunesta) Chemically unrelated to benzodiazepines Act specifically at the α1 subunit to facilitate GABA mediated transmission. Relieve sleep-onset insomnia Short duration of action and specificity less daytime sedation less tolerance and dependence (?able) CV and Respr depression w/ etoh barbs  Non-Benzodiazepine agonists Zolpidem (Ambien) CR-adds 2 hrs ½ life 1.5-3hrs. Good for 1 sleep period Morning sedation, anterograde amnesia Zaleplon (Sonata) ½ life 1hr. Very short acting, no side effects; no tolerance, rebound insomnia or dependence Eszopiclone (Lunesta) ½ life 6hrs, can be used for long term treatment of insomnia. Not as selective (but still lacks anxiolytic, anticonvuls..) No active metabolites so less daytime sedation Weird sleep behaviors: driving, eating, sleep crime, tweeting crimes  Antagonist Flumazenil (Romazicon) A competitive antagonist for the BZD receptor site. Antagonizes the effects of BZDs, Non- benzodiazepines Use: I.V. Overdose or anesthesia reversal Side effects: agitation, confusion…precipitate withdrawal Q: if a person ODs on a BZ and has not taken anything else should we administer Flumazenil?  Suvorexant (Belsomra) Orexin Receptor antagonist Orexin promote wakefulness narcoleptics lack orexin producing neurons Ramelteon (Rozerem) and Melatonin Agonists of melatonin receptors (MT1 and 2 agonist) to decrease sleep latency  Other Classes used as Anxiolytics Antidpressants: Serotonin in anxiety SSRIs like escitalopram (Lexapro) Antipsychotics Atypicals with serotonin activity Quetiapine (Seroquel) Aripiprazole (Abilify) Antiepileptics Gabapentin: blocks voltage gated calcium channels and reduces amygdala glutamate Autonomic agents: Propranolol or clonidine  ADHD ADHD Behavioral disorder primarily in children (5% and > boys) mostly resolves in childhood but it does affect adults (2.5%) Motor activity Sustaining attention Impulsiveness Symptoms dictate Inattentive type Hyperactive/impulsive type Combined  Symptoms Lead to social problems Education, relationships, self esteem, substance abuse Comorbid with Bipolar disorder (maybe as many as 20% of ADHD) Age, consistency, triggers are related to events, duration, family Depression (30%), Oppositional defiant disorder (ODD, 50-80%), anxiety disorders (20-40%), learning disabilities  Neurobiological basis Structural changes in Basal ganglia Reductions in PFC, caudate nucleus, corpus callosum and cerebellar volumes. changes in DA and serotonin receptors/transporter function/number Reduced function in the dorsolateral pre-frontal cortex and/or limbic region so they lack attention and executive function and impulse control Related to dopamine/noradrenergic dysfunction Multiple genetic and environmental risk factors leads to a heterogeneous disorder with high comorbidity and patient variability of symptoms and responses to therapy.  Neurobiological basis Normally NE and DA produce tonic moderate signals in the PFC which activate α2A and D3 then D1 receptors improving PFC function and communication to BG. In ADHD the activation is too low or out of balance. Agents that increase NE and DA in the PFC or increase the tonic firing of the neurons improve PFC function and reduce symptoms. If too much NE and DA is released then adrenergic receptors can be activated leading to inability to distinguish the proper signal in all the noise leading to inattention impulsivity, anxiety; D2 in nAcc lead to euphoria/abuse Too little or too much NE and DA will increase noise (distractions) and reduce signal (focus) Balanced increase in NTs improves signal:noise.  Treatment There are either stimulants or non- stimulants Drugs of choice are the stimulants Better than just therapy and non-stimulants Therapy plus drugs is better than drugs alone Improvements in Social skills, relationships and education CBT in preschool age 5-6 recommended first if needed phenidates are recommended If severe symptoms, then pharmacological  Stimulants Amphetamines: L-Amphetamine, d-amphetamine (Adderall) Lisdexamfetamine (Vyvanse) Phenidates: Methylphenidate (Ritalin) Metadata and Concerta (once daily) Daytrana (transdermal) Dexmethylphenidate (Focalin)  Stimulants Stimulants of CNS and sympathetic nervous system. Orally active and readily cross the BBB. Main action is to increase the synaptic concentrations of dopamine and norepinephrine. Higher doses 5-HT actions— Higher also increased motor, euphoria and abuse potential 65%-75% effective at improving hyperactivity, inattentiveness and impulsivity Many formulations  Amphetamines Mechanism Increase the release of DA + NE 1) Reduced reuptake via competition 2) increased non-vesicular release 1) vesicular displacement of transmitter (DA and NE accumulate in cytoplasm) 2) TAAR1 activation and phosphorylation of DAT 3) reverse transport: The transporter works in the opposite direction. 4) Dumping Figure  Amphetamines Mechanism Increases of DA + NE in the PFC improves signal to noise allowing for proper function. Increases of DA in the nucc accumbens can lead to abuse generally at higher doses and pulsatile frequent dosing Dextroamphetamine is 3-4xs more potent DAT and same for NET  Lisdexamfetamine dimesylate (Vyvanse) Prodrug that is metabolized to the active component. L-lysine is attached to d-amphetamine. After absorption d- amphetamine is liberated and exerts the therapeutic actions as described on previous slide. Also approved for Binge eating disorder. The benefits of this agent are purported by the company (Shire pharmaceuticals U.K.) to be: Less dependence and abuse Long lasting action- one dose being effective for 12 hrs. Available in extended release and Immediate release. Efficacy similar to other stimulants  Amphetamines Give feelings of alertness, euphoria confidence—Dopamine mostly Addiction, withdrawal and tolerance Peripheral actions due to NE Increased Systolic and diastolic pressures cause reflex bradycardia Arrhythmias can occur Obesity Used but not so useful Decrease intake; they do not increase metabolism. Tolerance develops to this action and any weight lost is usually temporary  Methylphenidate (Ritalin) Dexmethylphenidate (Focalin) Mechanism: Allosteric block of the DAT and NET at central synapses in brain stem arousal system and PFC again increasing communication to BG No reverse transport Same degree of CNS stimulation as amphetamine but without the increased motor activity and less cardiovascular stimulation unless in overdose. Lower abuse than amphet Recommended 1st line in preschool aged child Methylphenidate is also used for narcolepsy. Focalin more potent  Adverse effects of stimulants Insomnia, abdominal pain, anorexia, headache, sadness and irritability Reduced with use More significantly: growth suppression precipitation or exacerbation of tics (Gilles de la Tourette’s is a comorbid condition) Precipitation of psychosis/aggression with DA actions Tachycardia (direct sympathetic on heart) and changes in blood pressure. Tolerance Addiction (use of other non-stimulants)  Guanfacine (Intuniv) Alpha-2 agonist (remeber α2a stim in PFC improves signal to noise ratio). 1/day (lower efficacy and only in refractive pts. or patients with addiction problems) less hypotensive and sedative effects than w/ clonidine (can be used). Benefit with comorbid tics