Sedative & Hypnotics Antipsychotics

By Ronica Psychosis/Schizophrenia - high dopamine

Parkinson’s - low dopamine
● Hypnosis - high dose
Dopamine - inhibitory
● Sedation & Anxiolysis - Low doses
● NS pathway - motor
● Benzodiazepine (-pam)
○ Parkisonism related
○ frequency, GABAa: 2a, 2b, 1g
● ML/MC - behavioral
○ Flumanezil - anti-dote for -pam and
○ Anti-psychotic actions
zzz drugs
● Tuberohypo - endocrine, prolactin
● Barbiturates (-barbital)
● Medullary-periventricular - eating
○ duration, higher dose → affects
● Incerto - copulatory
GABAa directly
● D2 RECEPTORS - D2 D3 D4
○ Least selective to GABAa receptor
○ G-protein, decreases cAMP
isoforms
○ Inhibits Ca, opens K, pre and post
○ Thiopental
synaptic
■ can induce enzyme activity
● Schizophrenia - high dopamine
when used on long term
○ Positive: High dopamine in ML
basis
(PHLT)
● Phenobarbital
○ Negative: Low dopamine in MC
○ excreted unchanged in the urine
(NLCA)
○ Cumulative effects can occur with
○ Drugs that increase dopaminergic
multiple dosing, alkalization
activity:
○ ONLY BIG RENAL EXC
■ Levodopa - precursor
● Cimetidine, flumazenil - CYP450 inhibitor
■ Amphetamines - releaser
● Rifampicin - CYP450 inducer
■ Apomorphine - receptor
● MOTZ - short acting, 3-8 hrs
agonist
● TELA - intermediate, 10 - 20 hrs
■ Cocaine - reuptake inhibitor
● DCCFQ - long acting, 1-3 days
○ Serotonin (Ser 2A) inhibits dopamine
● New agents
release
○ Eszopiclone
○ HYPOFUNCTION OF NMDA →
○ Zaleplon
INCREASES DOPAMINE IN
○ Zolpidem
MESOLIMBIC PATHWAY
○ No anti-seizures, muscle relaxant,
■ Phencyclidine
decrease in sleep onset latency,
● schizophrenia like
phase 1 metabolism only, no active
symtoms,
metabolites, no anxiety but trouble
N-methyl-D-aspartate
sleeping, bind only to GABA A
receptor antagonism
receptor with isoform alpha 1 sub-
■ Amantidine
unit only, abrupt cessation →
● weak antagonist of
rebound insomnia
NMDA receptor
○ Dependence - physical or cognitive
○ Traditional antipsychotics - bind to
symptoms
D2 50x more
○ Physiologic dependence - need the
drug to feel better
Anti-psychotic agents
● Benzodiazepines and carbamates - muscle
● Well-absorbed, sequester in body tissues,
relaxants
have long half-lives, & require metabolism
● Alprazolam - anxiety (or anxiety-insomnia),
for elimination
panic disorder, and AGORAPHOBIA
Older/1st gen/TYPICAL - dopamine antagonist
● Thiopental & Methohexital - anesthetic
○ Phenothiazine - “-zine”
adjuncts
■ Chlorpromazine - prototype
● Melatonin receptor agonists
● A1 - hypotension
○ Ramelteon & Tasimelton
■ Thioridazine
● Phenytoin - anticonvulsant
● Least potent
● Fluvoxamine - enzyme inhibitor
● Mesoridazine - more
● If a patient is taking both a BZD and a TCA,
potent, metabolite
then flumazenil is given, it can cause
● Old - Prolonged QT
arrhythmias or convulsions
interval
● Old agents - REM rebound
■ Trifluoperazine
● Chlordiazepoxide, diazepam, prazepam,
■ Perphenazine
clorazepate → Desmethyldiazepam
■ Fluphenazine
● Thioxanthene
○ Thiothixantine
● Butyrophenone - H
 ○ Haloperidol Tardive dyskinesia
■ weak, newest ● When D2 receptors in the NS are blocked
■ Highest affinity for D2, chronically
few autonomic effect, ● Long-term antipsychotic
greater ● Receptors are super sensitive/up-regulate
extrapyramidal effect (increase in number), Supersensitivity of
■ Highest bioavailability dopamine receptors
● Low potency - low D2 affinity, ● facial and tongue movements
systemic ● late-occurring toxicity caused by typical
● High potency - blocks D2, alpha 1, antipsychotics
muscarinic, serotonin 1, H1 receptor, Neuroleptic Malignant Syndrome
high D2 affinity, CNS ● Most dangerous SE of typical
Newer/ATYPICAL - serotonin-dopamine ● Excessive rapid blocking of dopamine
antagonist (5HT2A) receptors —> severe EPS
● Molidone ● muscle rigidity -> impaired sweating -> high
● Loxapine fever
● Risperidone ● Autonomic instability, BP, HR
● Pimozide ● Muscle damage —> elevated CPK
● Clozapine (prototype) ● Give dantrolene
● Quetiapine - improve the negative
symptoms of schizophrenia w/ dopamine antagonists, dopamine ↓ and Ach
● Olanzapine - Weight gain, dyslipidemia, action ↑ → EPS symptoms and Parkinsonism
and disorders of carbohydrate metabolism ● Less anticholinergic effect - more EPS
● Aripiprazole - partial agonist of D2 and
5HT1A Newer/ATYPICAL - serotonin-dopamine
antagonist (5HT2A)
● Low EPS, efficacy for negative symptoms
● Serotonin inhibits dopamine production
● Proffered drugs

● Sertindole & Ziprasidone

○ Prolonged QT or QTc interval with
increased risk of dangerous
arrhythmias (Torsades de Pointes)
like Class 1A, azithromycin
● Clozapine
○ for treatment resistant schizophrenia
weight gain, sedation, seizures, or
agranulocytosis, Patients receiving
clozapine must have weekly blood
● Sedative action - S1 receptor blockade
counts for the first 6 months of
● Hypotensive action - a1 adrenergic receptor
treatment and every 3 weeks
blockade
thereafter.
● Muscarinic blockade - dry mouth
● Chlorpromazine or Mesoridazine
○ protruding tongue, grimacing, and
○ orthostatic hypotension
spasmodic torticollis
● Clozapine and Olanzapine - weight gain
● Chlorpromazine - cataract
● Thioridazine
○ “BROWNING OF VISION”, OD -
Neuroleptic Induced Deficit Syndrome
ventricular arrhythmias
● Increase in negative symptoms
● Ziprasidone
● Mesocortical pathway
○ greatest risk of QT prolongation
● NLCA
● Thioridazine and Ziprasidone
Drug-induced Parkinsonism and EPS
○ Quinidine-like action
● Nigrostriatal pathway
Indications:
● Give BENZTROPINE, anti-muscarinic type
or with Amantadine
 ● Older drugs except thioridazine - antiemetic ○ CYP2D6 → desvenlafaxine
effect ○ Lowest protein binding
● Phenothiazines - relief of pruritus ○ CARDIAC TOXICITY
● Promethazine - pre-op sedative ● Desvenlafaxine
● Thioridazine - anticholinergic, intractable ○ 45% unchanged in urine
hiccups ● Duloxetine
● Risperidone, Olanzapine, Quetiapine – ○ Hepatic impairment
good S/E profile and lower risk of tardive ○ 97% tightly bound to protein
dyskinesia (vs Haloperidol) ○ CYP2D6 and CYP1A2
● Lithium - mood stabilizer ○ Hepatotoxicity
○ Urinary stress incontinence
Lithium salts - prophylaxis in manic-depressive ● Milnacipran
episodes ○ Lowest protein binding
● Acts in Na in the body, alters IP3 levels, ○ Fibromyalgia
muscarinic and a adrenergic transmission, ● Levomilnacipran
G protein
● Very toxic with narrow therapeutic index
SNRI: Ve Le De Du Mil
(0.8-1.0), effect After 10 days
● Inhibition of vasopressin, causes diabetes
insipidus, blocks ADH Tricyclic antidepressants (TCA) - +anticholinergic
● Hypothyroid goiter - inhibits hormone effects, CYP2D6, ANTICHOLINERGIC,
release ANTIHISTAMINE, ALPHA RECEPTOR INHIBITION
● Teratogenic - cardiac malformation (Epstein Tx: unresponsive depression
abnormality) A/E: anticholinergic effects, alpha-blocking property,
● Renal excretion H1 antagonism, arrythmogenic, highly serotonergic,
lethality in overdose, prominent discontinuation
syndrom (cholinergic rebound or flu), LETHAL
Antidepressants ARRYTHMIA (Na bicarbonate), not for suicidal
SSRI - PTSD, bulimia, AE:sexual dysfunction,
SERT Tertiary amines - block the reuptake of both SER
● Sertraline and NOR, strong SER effect initially
○ Discontinuation syndrome, short HL ● Amitriptyline
○ Highest protein binding, lowest ● Imipramine
bioavailability ○ Highly anticholinergic
● Fluoxetine ● Clomipramine
○ Norfluoxetine ○ More SERT, less NET
○ + MAOI = serotonin syndrome, 4 ○ For OCD
weeks ○ Sexual effects are more common
○ Inhibitor of CYP2D6 ● Trimipramine
● Fluvoxamine ● Doxepin
○ inhibitor of CYP3A4 ○ Insomnia, pruitus
● Citalopram Secondary amines - block reuptake of NOR, less
● Escitalopram anticholinergic, lack active metabolite, linear
○ 4 weeks before effect kinetics
● Paroxetine ● Nortriptyline
○ Inhibitor of CYP2D6 ● Desipramine
○ Weight gain ● Maprotiline
○ Cardiac septal defect, category D
○ Discontinuation syndrome, short HL
TCA:
Tertiary amines: DICTA
SSRI: Secondary amines: NDM
Effective – Escitalopram
For – Fluoxetine, Fluvoxamine 5-HT2 Antagonist - blocking of serotonin receptors
Sadness – Sertraline → continuous release of dopamine
Panic – Paroxetine For: ​Antianxiety, antipsychotic, and antidepressant
Compulsions – Citalopram effects, major depression, unlabeled sedation and
hypnosis
SNRI - NET and SERT inhibition, increase in A/E: GIT disturbances, alpha-blocking (OH)
serotonergic and adrenergic, for GAD, pain ● Nefazodone
disorders (neuropathies, fibromyalgia); A/E: ○ Blocks SERT and NET weakly
Noradrenergic effects (increased BP and HR), ○ HIgh 1st pass effect, lowest
discontinuation syndrome bioavailability, shortest HL
● Venlafaxine ○ Inhibitor of CYP3A4
○ Weak inhibitor of NET ○ Hepatotoxicity
 ● Trazodone Monoamine oxidase inhibitors (MAOIs):
○ More SERT, less NET unresponsive major depression, extensive FPE
○ Metabolite is A/E: orthostatic hypotension, weight gain, sudden
m-chlorphenylpiperazine (m-cpp) discontinuation syndrome, PSYCHOTIC
(potent 5-HT2A,2C antagonist)​​ SYMPTOMS, SYMPA overstimulation,
○ A/E: Sedation HYPERADRENERGIC SYMPTOMS
● Vortioxetine
○ For cognitive dysfunction associated MAO-A: found in dopamine and NOR neurons;
w/ major depression substrates: NOR, EPI, SER
○ Inhibits SERT ● Moclobemide
○ Inhibitor of CYP isoenzymes ○ Reversible, selective MAO-A
○ Linear kinetics inhibitor
○ Sexual dysfunction (serotonergic) ○ Can be displace by high tyramine
MAO-B: found in serotonergic and histaminergic
neurons; acts on dopamine, tyramine,
5HT2 antagonist: TraVorNe
phenylethylamine, and benzylamine
● Selegiline
Tetracyclics & Unicyclics ○ Low dose: irreversible selective
● Amoxapine MAO-B inhibitor
○ inhibitor of the postsynaptic D2 ○ High dose: Nonselective MAOI,
receptor - antipsychotic effect transdermal, sublingual
○ Resemble TCA: NET>SERT ○ For parkinsons disease
○ Hepatic metabolism Both MAO-A & MAO-B: metabolize tryptamine
○ Parkinsonian syndrome ● Phenelzine, Tranylcypromine, Isocarboxazid
● Bupropion ○ Irreversible, nonselective MAOIs
○ Increased norepinephrine and ○ Phenelzine: sedation
dopamine activity ○ Sexual dysfunction
○ Presynaptic release of
catecholamines
○ Smoking cessation Both MAO A and MAO B: PTI
○ 3 active metabolites, biphasi
elimination ● Alpha 1 blocker: orthostatic hypotension
○ Agitation, insomnia, and anorexia ● H1 antagonist effect: sedation
○ Fluoxetine increase plasma ● Antimuscarinic effect: sympathetic
concentration (mydriasis, dry mouth, constipation, urinary
○ Seizures in OD constipation, palpitation, tachycardia)
● Maprotiline
○ Resemble TCA: NET>SERT
○ Hepatic metabolism
○ TCA-like adverse effect
● Mirtazapine
○ Antagonist of the presynaptic alpha
2 autoreceptor → increased release
of norepinephrine, 5-HT
○ ​Antagonist of 5-HT2A, 5-HT2C, and
5-HT3 receptors; potent H1
antagonist
○ Sedation, disorientation, tachycardia
○ HL: 20-40 hrs, lowest bioavailability
● Vilazodone
○ ​Potent serotonin reuptake inhibitor
○ Partial agonists of the 5-HT1A
receptor
○ Absorption is sincreased with a fatty
meal
○ GI upset
● Buspirone
○ Partial agonists of the 5-HT1A
receptor
○ Antidepressant and anxiolytic

Tetracyclic and unicyclic: MaMir Vila AmBuBus

FIRST-LINE: SSRIs and SNRIs (Bupropion &
Mirtazapine)
SECOND- or THIRD-LINE: TCAs and MAOIs
Remission/Relapse: 4-9 months

● PTSD: SSRI
● OCD: Clomipramine
● Social anxiety: SSRI & venlafaxine
● Premenstural Dysmorphic Disorder:
SSRI (Fluoxetine and Sertraline)
● Postpartum depression: Sertraline
● AD: for bulimia, not anorexia
● Bulimia: fluoxetine
● Hot flashes: Desvenlafaxine, SSRI
(venlafaxine, nefazodone)
● Bupropion: smoking cessation, obesity, tx
of sexual adverse effects, premature
ejaculation, CAN LOWER SEIZURE
THRESHOLD, anxiety

Dosing
● Depression - therapeutic dose
● OCD - maximum
● Panic disorder - minimum dose of
paroxetine, higher than minimum
● Pain w/ neuropathy - imipramine,
subtherapeutic dose

Interactions
● Fluoxetine - TCAs → toxicity
● Fluoxetine - MAOI
○ 4-5 weeks
● MAOI - serotonergic agent
○ 2 weeks
● Tyramine - MAOI → increase BP and stroke
● MAOI - sympathomiemtics or bupropion