Medical Archive

C29.1 General Principles of Psychopharmacology

BZD	??? ??, TDI ? GABA, Cl channel? ???? GABA ?? ?
Buspirone	????? ?? ??????, ??, ??? X, BZD ??? ??? ? ??.
Propranolol	?????? TOC

Comparison

Class	Block	Benefits & indications	Analgesic	Sleep	Weight	Adverse effects	Contraindications
TCA	S, NE, α1, M		O	O		??? ???? ??.
SSRIs	S			X
MAOI	MAO (S, E, NE)	MDD+atypical feature, or TCA?			Gain	Hypertensive crisis, serotonin syndrome
SNRI	S, NE	Duloxetine	O			A/N/V
		Venlafaxine				A/N/V, HTN
NDRI	NE, D	Bupropion – stimulant		O	Loss	Tachycardia, insomnia	Seizure disorders, bulimia/anorexia nervosa.
NaSSA	S(5-HT2, 3), H1	Mirtazapine –		O	Gain
SARI	S, α1	Nefazodone Trazodone		O

Augmentation strategies
When a patient has experienced a partial response to an adequate trial of monotherapy.
Adding aripiprazole or bupropion

<Strategy>

• SSRI: assessment of response in 6-12 weeks after initial treatment
  • If response is minimal or significant S/E occurred -> cross-tapering
  • Lethargy, difficult concentrating, weight gain -> bupropion (NDRI)
  • Insomnia -> trazodone (SARI)

Chloral hydrate (??)
Zopiclone, Zolpidem
Short acting (Non BZ)
BZ ??? ?? ???? ??? ??. ?? ? ??.

	Amphetamine
	LSD, mescaline, cocaine, phencyclidine
	Brain activation?? grand mall seizure ??

??

??
Lithium
Indication: ??/?? ??, ??? ????(cyclothymia)
????? ?? ???(10-14?) ????? anti-? ???
Valproate
Indication: ???, ?? ???

Those with severe illness, often require combination therapy to maintain stability.
Lithium or valproate + second-generation antipsychotic (eg, quetiapine) is first-line combination therapy.

Class	Mechanism of action		Monitoring
Carbamazepine	Blocking sodium channels, alters central GABA receptors	Kindling effect? ? ??? ?. ???, Agranulocytosis	Blood level, rash
Valproic acid	Augmentation of GABA		Blood level, LFT
Second-generation antipsychotics	Quetiapine Lurasidone Lamotrigine	– – ?? antimanic ?? X. SJS? ??.
??		CCB, BZD, clonidine? ?? ?? SSRI ? ? ?? ?? ??, SNRI? ?? ??!!

??

Dopamine ?? – Dopamine, serotonergic nerve? dysfunction? ???? ??.
?? – BBB ????. ???? ?? ?? ???
D2 block ??. Mesocortical: ?? ?? / Mesolimbic: ?? ??
4~6?? ???? ?? ? ?? ??? ?? (??? ???? ??)
?? ?? ?? ?? ?? ????.
??? ???? 4? ?? haloperidol IM
???? ?? ??. ????? atypical anti-??.
?? 1st trimester?? ???? ??.

Indication
Schizophrenia and other psychotic disorders
Hiccups, Tourette syndrome, and bipolar disorders
 
FGA (typical) – Dopamine D2 ??? ??
Movement, prolactin side effects.

SGA (Atypical) – Serotonine 5-HT2A ??? ??
Weight gain, increased risk of diabetes, and metabolic syndrome, but also cause movement and prolactin side effects.

Potency? ?? ??

Low: Chlorpromazine, clozapine, olanzapine
High: Risperidone(2nd gen), Haloperidol(1st gen)

Side effects	Peak	Characteristics	Management
????		m/c. ??? ???? ?
????		???, ??, ??? ???, ??? ??

Long-acting injectable (depot) antipsychotic

• Not an appropriate initial intervention. Conversion to this could be considered once the patient is stabilized on oral antipsychotics in the hospital.
• Examples
  • Haloperidol decanoate – every 28 days
  • Fluphenazine decanoate – every 21 days
  • Flupenthixol decanoate
  • Zuclopenthixol decanoate
  • Aripiprazole monohydrate
  • Olanzapine pamoate
  • Paliperidone palmitate
  • Risperidone LAI – every 14 days

C29.2 Medication-Induced Movement Disorders

EPS

Striatum? dopaminergic-cholinergic balance? ??? ??.
D2: inhibitory (nigrostriatal)
M1: excitatory

Acute dystonia	4hr to 4d	?? ????? ?? ???, ?? ???, ?? ???	IM Benztropine PO Benztropine PO Diphenhydramine
Parkinsonism (rigidity)	3 wk		PO Benztropine Amantadine
Parkinsonism (tremor)	6 wk		PO Benztropine Amantadine
Akathisia	10 wk		Propranolol PO Benztropine Lorazepam

Amantadine is also used in Parkinsonism.
A dopaminergic medication, but usually does not worsen psychosis.

Neuroleptic malignant syndrome

• Pathophysiology
  • Dysregulation of dopamine caused by D2 receptor antagonism.
  • Typically begin within 2 weeks of initiation, but can occur at any time during treatment.
  • ??? ???? ?????.
• Signs/symptoms
  • Fever, confusion, muscle rigidity (generalized)
  • Autonomic instability (abnormal vital signs, sweating)
  • cf) serotonin syndrome – neuromuscular hyperactivity rather than rigidity (eg, tremor, hyperreflexia, myoclonus)
• Lab
  • ?serum CK, WBC count
• Treatment
  • ??? ?? ? ????, ?? ???.
  • Dantrolene
    • ? ???. Antagonizes ryanodine receptors – inhibits calcium release form the SR.
  • Bromocriptine
    • Dopamine agonist

Tardive dyskinesia

• > 3-6 month
• Etiology
  • Hypersensitive post-synaptic D2 receptors
  • Imbalance between D1 and D2 receptor-mediated effects
• ???? ? ????? ?? ??? ?.
• Treatment
  1. Reducing the antipsychotic dose
  2. VMAT2 inhibitors
     • Valbenazine
     • Deutetrabenazine
  3. Switching (cross-tapering)
     • Lower tendency to cause TD, such as quetiapine or clozapine

Medication-induced postural tremor

Other medication-induced movement disorders

Nocturnal myoclonus
Restless leg syndrome

Hyperthermic syndromes

C29.3 ?2-Adrenergic Receptor Agonists, ?1-Adrenergic Receptor Antagonists: Clonidine, Guanfacine, Prazosin, and Yohimbine

C29.4 ?-Adrenergic Receptor Antagonists

C29.5 Anticholinergic Agents

C29.6 Anticonvulsants

C29.7 Antihistamines

C29.8 Barbiturates and Similarly Acting Drugs

C29.9 Benzodiazepines and Drugs Acting on GABA Receptors

Mechanism of action

Bind to GABA-chloride receptors, facilitating the action of GABA.
Depression of the CNS at the limbic system, RAS, and cortex.

Characteristics

??? ??, TDI ?

Long-acting
? Half-life > 50hr
? Associated with prolonged side effects – should be avoided when trying to minimize side effects.
? Diazepam, chlordiazepoxide, flurazepam
Intermediate-acting
? Half-life 6-50hr
? Oxazolam, alprazolam, lorazepam (12hr), clonazepam
Short-acting
? Half-life < 6hr
? Higher addictive potential
? Triazolam, midazolam
Patients with liver disease
? Lorazepam, temazepam, oxazepam

Side effects

Disinhibition? ?? ??? ??, ????
???/??? ?? ? ???? ???? ?? ?
? TCA ? imipraimine? ????? ?? ????/?? ???? ? ???.

Zolpidem, zaleplon, eszopiclone

Short-acting nonBZD hypnotic agent.
Do not produce the anxiolytic, muscle relaxant, or anticonvulsant effects associated with BZD.

C29.10 Bupropion

Mechanism

Relatively weak inhibitor of the re-uptake of NE and D
Does not inhibit the re-uptake of serotonin
Stimulates 5-HT1A receptors
?? ?????? 1-2? ??

Activating antidepressant; could increase anxiety and insomnia.

Toxicity

? Stimulant effects
? Tachycardia, insomnia
? Headache, seizures in anorexic/bulimic patients
? Barbiturate, BZD?? ?? alcohol? interact ??.
? ????, ??? ??? ?? ??.
? ??, ????, ??? ??? ??.

C29.11 Buspirone

Mechanism of action

Partial agonist of the 5-HT1A, which act at GABA-A receptors.

Characteristics

• Full effect is seen >7 days – not useful in the acute setting!
• ????? ?? ???? ??, ??, ??? X
• ?Risk of dependence, ?side effects, ?anxiolytic effects
• Indication
  • Augmentation therapy when anxiety is not well controlled with SSRIs.
  • BZD ??? ??? ?

C29.12 Calcium Channel Blockers

C29.13 Carbamazepine and Oxcarbazepine

Mechanism of action

Blocking sodium channels, alters central GABA receptors

Side effects

GI distress, rash, mild leukpenia, agranulocytosis, aplastic anemia
If toxic, may cause hypotension, tachycardia, respiratory depression, or coma.
?? ?? monitoring? ??.

C29.14 Cholinesterase Inhibitors and Memantine

C29.15 Disulfiram and Acamprosate

C29.16 Dopamine Receptor Agonists and Precursors

C29.17 Dopamine Receptor Antagonists (First-Generation Antipsychotics)

Mesocortical dopamin pathway ???? ????
Therapeutic index? ?? ??

Chlorpromazine, Thioridazine
EPS?, ?? ?, ??? ?
?? ???, ?????
Haloperidol, Trifluoperazine, Fluphenazine
EPS?, ???, ???

? ? Perphenazine, Loxapine ???

Ophthalmologic adverse effects
Chlorpromazine: corneal deposits
Thioridazine: retinal deposits

Fluphenazine

• Impaired thermoregulation
  • d/t the effects on the hypothalamus, which leads to inappropriate response to heat or cold
  • Who are likely to be exposed to extreme temperatures (e.g., those who are homeless) should be monitored.

C29.18 Lamotrigine

C29.19 Lithium

Physiology

• Inositol depletion ? 2nd messenger ?

Lithium ????? ?? ???(10-14?) ????? antipsychotics ???
Loop diuretics? ?? ??? ???? ?.

Side effects

Dose-independent, general adverse effects

• Nonspecific
  • Nausea (10-20%), diarrhea
  • Weight gain 
  • Dry oral mucosa
  • Leukocytosis
• Motor
  • Fine tremor (~25%)
    • Nonprogessive, symmetric, fine (~10Hz) postural tremor in the distal ends of upper extremities 
    • Typically occurs when lithium therapy is started or the dose is increased but can occur at any time during the course of treatment
    • Often decreases spontaneously over time
    • If persists, a reduction in the dose, the use of short-acting lithium preparations, and/or divided doses can be considered.
    • If refractory, BB.
  • Muscle weakness
• Dermal
  • Acne
  • Worsening psoriasis
  • Hair thinning
• Cardiac
  • ECG changes: T-wave depressions (most common), U waves, repolarization abnormalities
  • Sinus node dysfunction (eg, sinus bradycardia -m/c, SSS)
• Thyroid
  • Hypothyroidism  (~25%)
    • ??/?? ?? ?? T4 replacement ?? ??
    • TSH testing repeated every 3 months
  • Hyperthyroidism (rare)
    • Goiter (particularly in second and third trimester of pregnancy)
  • Hyperparathyroidism causing hypercalcemia
• Renal
  • Nephrogenic diabetes insipidus
    • Pathophysiology: lithium interferes with ADH signaling ? reduces aquaporins (water channels) on the collecting duct cell’s surface ? fewer water molecules are reabsorbed and kidneys are unable to concentrate urine ? increased free water excretion
    • Clinical features: polyuria, nocturia, and polydipsia ? increased risk of dehydration and subsequent lithium toxicity
  • Chronic interstitial nephritis (lithium-associated nephropathy)
    • Interstitial fibrosis, focal nephron atrophy, tubular cysts with chronic use
    • Risk correlates with the cumulative dose and duration of lithium use.
    • Often occurs in the setting of nephrogenic DI
    • Can progress to chronic kidney disease
• Teratogenicity: cardiac malformations, in particular Ebstein anomaly

Dose-dependent toxicity

0.8-1.2 mEq/L	?? ??!
1.5-2.0 mEq/L	A/N/V/D
2.0~2.5 mEq/L	A/N/V/D, blurred vision
>2.5 mEq/L	Generalized convulsion -> dialysis

• Acute toxicity
  • Gastrointestinal (eg, N/V, diarrhea)
  • Late neurologic sequelae
• Chronic toxicity
  • Neurologic (eg, lethargy, confusion, agitation)
  • Ataxia, tremor/fasciculations, seizure
  • Can be precipitated by volume depletion and drug interactions with Thiazide, ACEi, NSAIDs
• ?Risk
  • Dehydration from any cause (eg, vomiting, diarrhea, fever, diuresis)
  • Elderly (low GFR, ?volume of distribution)
  • Medications
    • ?Renal perfusion, ? lithium clearance
    • ACEi, NSAIDs, thiazide diuretics, tetracycline, metronidazole
• Hemodialysis
  • Patients with lithium levels >2.5 mEq/L and prominent signs of toxicity
  • Patients with lithium levels >4.0 mEq/L and creatinine >2.0 mg/dL regardless of symptoms.

Monitoring

6-12???? RFT, TFT ??

C29.20 Melatonin Agonists: Ramelteon and Melatonin

Binds MT1 and MT2 in suprachiasmatic nucleus.
Adverse effects: dizziness, nausea, fatigue, headache
No dependence

C29.21 Mirtazapine (NaSSAs)

Mechanism

? Alpha 2 antagonist
? Stimulates NE and 5-HT release
? Blocks 5-HT2, 5-HT3, H1

???? – ??? ??? ???
?????, ??????

C29.22 Monoamine Oxidase Inhibitors

Clinical use

• Major depressive disorder(MDD)
  • Treatment-resistant MDD
  • MDD with atypical features
• Anxiety
• Parkinson disease (selegiline)

Phenelzine, selegiline

Adverse effects

• D/t CNS stimulation
• Hypertensive crisis
  • Problem foods: aged cheese, dried fish, sauerkraut, sausage, chocolate, avocados, red wine.
  • Safe foods: cottage cheese, some wine (mostly white)
• Serotonin syndrome
  • CIx with SSRIs, TCAs, St.John?s wort, meperidine, dextromethorphan
  • ?? serotonergic drug? ?????? 2?? ?????.

C29.23 Nefazodone and Trazodone (SARIs)

5-HT2, ?1, H1 blocker
?? ??? ??.

Side effects

Almost no anticholinergic adverse effects.
Priapism -> used to treat erectile dysfunction.
Can cause sexual dysfunction like SSRI.
Sedation is common.

C29.24 Opioid Receptor Agonists

Mechanism

? Act as agonists at opioid receptors (? = ?-endorphin, ? = enkephalin, ? = dynorphin) to modulate synaptic transmission
? Close presynaptic Ca 2+ channel, open postsynaptic K + channels ? ?synaptic transmission.
? Inhibit release of ACh, NE, 5-HT, glutamate, substance P.

Full agonist: morphine, heroin, meperidine, methadone, codeine.
Partial agonist: buprenorphine.
Mixed agonist/antagonist: nalbuphine, pentazocine.

Pentazocine

?-opioid receptor agonist and ?-opioid receptor weak antagonist or partial agonist.
Analgesia for moderate to severe pain.
Can cause opioid withdrawal symptoms if patient is also taking full opioid agonist (due to competition for opioid receptors).

Butorphanol

?-opioid receptor agonist and ?-opioid receptor partial agonist.
Severe pain (eg, migraine, labor). Causes less respiratory depression than full opioid agonists.
Use with full opioid agonist can precipitate withdrawal. Not easily reversed with naloxone.

Tramadol

Very weak opioid agonist; also inhibits 5-HT receptors.
In chronic pain.
Adverse effects: Similar to opioids. Decreases seizure threshold. Serotonin syndrome.

C29.25 Opioid Receptor Antagonists: Naltrexone, Nalmefene, and Naloxone

C29.26 Phosphodiesterase-5 Inhibitors

C29.27 Selective Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Duloxetine

???? ???? ??, ??? ???? ??. A/N/V
Also indicated for fibromyalgia

Venlafaxine

??? ??? A/N/V ????, ?????

Side effects

• Hypertension
  • Dose-dependent. BP should be monitored regularly
  • Especially significant at doses >300mg daily, in which the incidence may be >10%
• Stimulant effects, blurry vision (common)

C29.28 Selective Serotonin Reuptake Inhibitors (SSRIs)

Indication

MDD ??? anxiety, sexual disorders ??? ????.
REM ??? ????? ??? X, (?????) ????? ?

Characteristics

• ?? ????? 4-8? ??. ??? ???? ??? mania? ??.
• ?? ??? ??? washout period? ????. Fluoxetine? 5?, ???? 2?.
• Stimulating effect
  • SSRI-induced activation of presynaptic 5HT1A ? inhibition of serotonin release and a net ? in serotonin levels before the full effects of the medication.
  • Temporary dose reduction with the goal of improving tolerability.
• Treatment-resistant
  • Failure to respond to at least 2 adequate antidepressant trials
• Continuation-phase treatment
  • Achieved remission after acute-phase treatment with sertraline.
  • To decrease the risk of depressive relapse, recommend continuing antidepressant treatment for an additional 6 months in patients with remitted single-episode, unipolar major depression. The dose should not be reduced.
• Maintenance-phase treatment
  • Maintenance for 1-3 years is appropriate for patient with a high risk of recurrence (eg, >2 episodes, persistent residual depressive symptoms)
• Complete remission
  • Maintained at the end of the continuation phase, the antidepressant can then be tapered gradually and discontinued.

• Fluoxetine
  • ‘???’ ?? ? ???
  • ??? ?? SSRI? ?? ?? ?? ??, ????? ?? ???? ???, ??? ???? ??? ???? ??? ??? ??. ?? ?? ?? ? ?? ??? ?? ?????
• Sertraline
• Paroxetine
  • ?? ??????, ??? ?? ??.
• Fluvoxamine
• Citalopram
  • ?? SSRI ??? ?? ????? ??????? ?? ?? ???. ?? ???? ???????? ???? ??? ? ?? ???? ???.
• Escitalopram
  • ?????? ???? ????? ????? s-????? ??? ????. ??????? ????? ?????? ? ???? ? ?? ???. ????? ???(?????)? ??? ?? ?? ???? ?? ?? ? ????. ???, ???? ?? ?? ???? ???? ?? ????[3] ???? NICE??? ???? 1? ???? ?? ???? ??.
• Vilazodone
  • Inhibits 5-HT reuptake, 5-HT1A receptor partial agonist.
• Vortioxetine
  • Inhibits 5-HT reuptake, 5-HT1A receptor agonist, 5-HT3 antagonist.

Side effects

Sexual dysfunction
In > 50%, ????/????(+sildenafil or bupropion)
Weight gain, headaches, GI complaints, ??

Serotonin syndrome

• Etiology
  • Associated with high doses, MAOI/SSRI combo, MAOI/synthetic narcotic combination.
  • Or serotonergic medication combination with non-antidepressant with MAOI activity (e.g., linezolid)

• Clinical features
  • Similar symptoms with NMS, but onset <1 day, hyper-reflexia, clonus (not rigidity)
  • General restlessness, sweating, insomnia, nausea, diarrhea, cramps, delirium, myoclonus.
• Treatment
  • Removal of the causative agent, stopping the SSRI, and administering cyproheptadine (5-HT2 receptor antagonist)
• Prevention
  • Most antidepressants should be discontinued 2 weeks before beginning an MAOI.
  • The SSRI fluoxetine is an exception d/t its long half-life and must be stopped 5 weeks before initiating an MAOI.

Withdrawal

• Discontinuation syndrome; ???, NV, ??, ??? ? ? 3? ? ?? ??

C29.29 Serotonin-Dopamine Antagonists and Similarly Acting Drugs (Second-Generation or Atypical Antipsychotics)

??? 1???? ????, ??? risk ? ????.
??? D2 ??? ??? 65-80%?? ??. ???? EPS

Comparison to FGA

• Equally effective in the treatment of positive symptoms.
• Both block muscarinic receptors
  • Low potency FGAs, SGAs have the greatest risk.
• Both have been associated with lowering seizure threshold.
  • Clozapine, in particular, has been associated with a dose-dependent increase in seizure risk.
• ?Tardive dyskinesia

	Weight gain / metabolic syndrome	EPS (including hyperprolactinemia)	Prolonged QTc
Clozapine	Very high	Low	Medium
Olanzapine	Very high	Low	Medium
Quetiapine	High	Low	Medium
Risperidone	High	High	Medium
Aripiprazole	Low	Low	Low
Ziprasidone	Low	Low	High
Lurasidone	Low	Medium	Low

S, D antagonists

• Clozapine, olanzapine
  • ??? clozapine, ??? olanzapine
  • Indication
    • Tardive dyskinesia? TOC
    • Treatment-resistant schizophrenia
      • Clozapine is the only one that has shown efficacy
    • Schizoaffective disorder
    • Suicidality in schizophrenia
  • Adverse effects
    • Agranulocytosis (neuropenia)
      • Only clozapine needs WBC monitoring – 1% risk
      • Weekly blood counts during the first 6 months of treatment.
    • Seizures
      • Clozapine – dose related
    • Metabolic syndrome
      • Clozapine & olanzapine is high risk
      • Weight gain
      • Diabetes
      • Hyperlipidemia
• Risperidone
  • ?? ??? ????? prolactin?, ????
  • Among SGAs, most likely cause EPS, especially higher doses.
• Quetiapine
  • Clozapine? ?? ??, ????? X
• Aripiprazole
  • ???? X, prolactin ???, ?? ?? X (partial dopamine agonist)
• Ziprasidone
  • ???? X, prolactin ???, ???(QT prolongation), ????

D2 selective RI (sulpiride)

C29.30 Stimulant Drugs and Atomoxetine

C29.31 Thyroid Hormones

C29.32 Tricyclics and Tetracyclics

TCA

NE, 5-HT? amine NT ?? – ?? ?, REM ?? ?? – ? ??.
Imipramine, nortriptyline, desipramine? ???? ??.

Indication
???? imipramine (S/E: Torsa de pointes)
???? clomipramine (S/E: anti cholinergic)
????, ??? ?

• Anticholinergic (M)
  • Tachycardia, urinary retention, dry mouth
  • Tertiary > Secondary
  • Confusion, hallucination in the elderly – nortriptyline is better.
• Antihistamine (H1)
  • ???, ??
• ?1-blocking effect
  • ??? ???
• Presynaptic (NE & 5-HT) neurotransmitter reuptake
  • Antidepressant & anxiolytic effects, seizures, tremors
• Blockade of cardiac fast Na+ channels
  • Prolonged PR/QT interval, arrhythmias (eg, ventricular tachycardia, fibrillation)
  • Widened QRS interval (like Ic group)
• Convulsion, Coma

3? ??: imipramine(?????), amitriptyline(????)
2? ??: desipramine, nortriptyline
New: Clomipramine, trazodone(???)

Management of intoxication

• Tintinalli

C29.33 Valproate

Mechanism of action

Augmentation of GABA in CNS

Indication

Bipolar disorder and rapid cycling bipolar disorders.

Side effects

Sedation, weight gain, tremors, alopecia, GI distress, and teratogenicity (neural tube defects)
If toxic, may cause confusion, coma, or cardiac arrest.
??? ??? ???? ???.

C29.34 Nutritional Supplements and Medical Foods

C29.35 Weight Loss Drugs