Classification:TCA

MOA:Inhibit reuptake of NE & 5HT by inhibiting NET & SERT (mixed & variable) + autonomic & histamine

Indication/Clinical Application:Depression, Major depression not responsive to other drugs, chronic pain.

SE & ADE's: see TCA (there are A's in Amitrip)

AChM: +++

Alpha 1: +++

H1: ++

5HT2: 0/+

NET: +

SERT: ++

Therapeutic Considerations: See TCA

lethal dose = 1500 mg (less than week's supply)

PK:

F = 45%, Plasma T1/2= 31-46 hrs, Active Metabolite T1/2: 20-92 hrs

Vd = 5-10 L/kg, Protein binding 90%

Classification:TCA

MOA:Inhibit reuptake of NE & 5HT by inhibiting NET & SERT & autonomic & histamine blockade

Indication/Clinical Application: see TCA + OCD (FDA approved) 

 SE and AED's: see TCA (clomp down and insert)

 sexual effects (SERT)

SERT: +++

NET: ++

Alpha 1: ++

ACh M: +

H1: +

5HT2: + 

Contraindications: see TCAs

Therapeutic Considerations: relatively little affinity for NET but potent @ SERT - contributes to known benefits of OCD

Classification: Tetracyclic antidepressant

MOA:Potent NET inhibitor and less potent SERT inhibitor (NET > SERT) ; acts like TCAs

Indication/Clinical Application:Rarely used due to side effects; Primary use is in MDD that is unresponsive to other agents

SE and AED's: ( all you need fo an adventure is a map, net, and a head honcho)

May cause TCA-like adverse effects & (rarely) seizures

anticholinergic and antihistaminic properties

NET: ++

H1: ++

Alpha1: +

ACh M: +

5HT2: 0/+

SERT: 0

Contraindications: 

Seizure,

electrolyte abnormalities, bulimia or anorexia, MAO inhibitors;

Shares most drug interactions common to the TCAs;

Should be used with caution in combination with CYP2D6 inhibitors such as fluoxetine

Therapeutic Considerations:

lowers seizure threshold;

PK:

 88% bound to protein,

Extensive hepatic metabolism (2D6),

F = 70%,

plasma t1/2 43-45

Vd= 23-27

2D6 substrate

Classification: TCAs

MOA: Mixed & Variable blockade of NET & SERT, blockade of autonomic NS & histamine receptors

Indication/Clinical Application:

Major depression not responsive to other drugs,

chronic pain disorders,

incontinence

Depression 

SE & AED's: (HAS SAD)

Anticholinergics (dry mouth, urine retention, blurred vision, confusion)

alpha1: orthostatic hypotension (elderly)

H1: sedation & wt gain

Sexual effects

Arrhythmias (NET)

D/C syndrome

Contraindications:Use w/ MAOi, Cardiac conduction Stem defects, Use in patients during acute recovery after MI

Interactions: CYP inducers & inhibitors, additive AntiACh, antiH1, and antiHTN effects w/ other drugs

Therapeutic Considerations:PM dosing, Can precipitate mania w/ biplar disorder. Toxic in Toddlers @ 100 mg

PK: Long T1/2, CYP2D6 Substrate, Extensive metabolism

Active metabolites, ONly 5% excreted unchanged in urine

Classification:tetra/uni antidepressants

MOA: see individual drugs

Contraindications:Sebem

Seizure, electryolyte abnormalities, bulemia or anorexia, MAOi

Therapeutic Considerations: specific to drugs

PK: highly protein bound, extensively metabolized in liver; Active metaboites: buproprion & amoxapine, 

Classification: TCA

MOA:

NET & SERT (relatively strong) + autonomic & Histamine blockade

Indication/Clinical Application:TCA +

migraine HA

chronic tatlgue syndrome

other somatic pain disorders

(neuropathy pain (25-50 mg/d)) - subtherapeutic dose

nocturnal enuresis 

SE and ADE's:

TCA + 

highly anticholinergic (++)

SERT: ++

NET: +

H1: +

Alpha 1: +

5HT2: 0/+

Therapeutic Considerations:

Lethal dose 1500 mg (< week's supply)

Has more serotonergic effects initially; metaolite desipramine later balances serotonergic effect w/ more NET inhibition

PK:

F = 40%, Plasma t1/2 = 9-24 hr,

Active T1/2: 14-62 hr,

Vd = 15-30 L/kg

Protein binding: 84%

Inhibitor of 2C19

Classification: TCA

MOA: H1, Alpha 1, Ach M, 5hT2

Indication/Clinical Application: see TCA

SE and AED's:

H1: +++

Alpha1: ++

Ach M: ++

5HT2: 0/+

SERT & NET: 0

Classification: TCA

MOA:

Alpha1: +++

H1: +++

ACh M: ++

NET/SERT: +

5HT2: 0/+

Indication/Clinical Application: see TCA +

hypnotic

pruritus 

SE and AED's:

see MOA (ortho, wt gain, sedation), TCA

Contraindications: TCA

Therapeutic Considerations: TCA

PK: TCA

Classification: Tetracyclic

MOA:

5HT2: +++

NET: ++

Alpha1: ++

SERT: +

H1: +

ACh M: + 

Actions resemble those of TCAs such as desipramine 

(NET > SERT)

Moderate inhibitor of D2 receptor (acitve metabolite)**

**Possesses some Antipsychotic properties

Indication/Clinical Application:

Commonly not prescribed for current practice; if so,

Refractory MDD

SE and AED's: similar to TCAs

Anticholinergic & AntiHistaminic 

Parkinsoniasm syndrome (D2-blocking action)

Contraindications:

drug-drug similar to TCAs

Therapeutic Considerations:

N-methylated metabolite of loxapine, similar structure to TCAs

Often given in Divided Doses

antiACh & AntiH1 properties - additive w/ other drugs

Lowers seziure threshold 

PK:

Plasma T1/2 = 7-12 hr

Active T1/2 5-30 hr (variable)

Vd = 0.9 - 1.2 L/kg

Protein binding: 85-90%

rapidly absorbed

Extensive Hepatically metabolized

Active Metaboite: 7-Hydroxyamoxapine (potent D2 blocker associated w/ antipsychotic effects) 

2D6 substrate

Classification:TCA (Noradrenergic Antidepressant)

MOA:

NET: +++

SERT: +

H1: +

Alpha1: +

ACh M: +

5hT2: 0/+

Indication/Clinical Application:

SE and AED's:

much less anticholinergic

Contraindications:

Therapeutic Considerations:

More potent & more selective NET inhibitor than imipramine

lacks active metabolites

Wide Therapeutic Window 

Serum levels are reliable in predicting resposne & toxicity

Metabolite of Imipramine 

PK:

linear PK

Classification: TCA

MOA:

NET: ++

SERT: +

5hT2: +

H1:+

Alpha1: +

ACh M: +

(NET > SERT)

Indication/Clinical Application: TCA +

Smoking cessation (not as consistent effects as buproprion) 

SE and AED's: TCA

Contraindications: TCA

Therapeutic Considerations:

Lacks Active Metabolite!

PK:

Linear PK (serum levels reliable in predicting response & toxicity)

wide therapeutic window

Classification: TCA

MOA:

NET: +++

AChM: +++

SERT: +

Alpha1: +

H1: +

5HT2:+

Indication/Clinical Application: TCA

SE and AED's: TCA

Contraindications: TCA

Therapeutic Considerations: TCA

Classification: SSRIs

MOA:

High SERT blockade

(acute incr. in serotonergic activity)

Slower changes in several signaling pathways & neurotrophic activity 

Little effect on NET

Indication/Clinical Application:

Major Depression

Anxiety Disorders

Panic Disorders

OCD

PTSD

Perimenopausal vasomotor symptoms (suggested)

Bulemia

SE & ADE's: 

Serotonin Sydrome (hypothermia, muscle rigidity, myoclonus, rapid fluctuation in mental actiivty & vital signs)

Sexual dysfunction

GI distress

HA

Somnoloence

Wt Gain

D/C Syndrome

Contraindications:

MAOis

Therapeutic Considerations:

May precipitate mania in bipolar patients

1st line agents treatment of depression, anxiety, and OCD

Significantly more selective for 5-HT transporters than TCAs

Fewer ADEs than tCAs

Have Greater Therapeutic Index 

PK:

T1/2 from 15-75 hrs

Oral activity

Highly Protein bound

CYP Inhibition ( can lead to elevated TCA levels & cause ditiazem-induced bradycardia/hypotension)

Classification: SSRI

MOA: 

highly selective blockade of SERT; Acute incr. of serotonergic synaptic activity

SERT: +++

5HT2: 0/+

Indication/Clinical Application:

Major Depression*, GAD*,PTSD, OCD*, Panic disorder* (w/ or w/o agoraphobia), PMDD (FDA), Bulimia (FDA)

SE and AED's:

Serotonin Syndrome**; may precipitate mania in bipolar patient; sex dysfunction, GI distress, HA, somnolence, Wt gain, D/C syndrome

Contraindications:

D/C for 4 weeks before starting MAOi**

Therapeutic Considerations:

1st Line for *; Made 1988; Racemate; Highly lipophilic; Easy to use, safeR in overdose, tolerable; 

Longest T1/2 (48-72) of all SSRIs;

Metabolized to active norfluoxetine (T1/2 3x Fluox);

One of the most commonly prescribed meds;

 Lead to high TCA [ ] if given together due to 2D6 inhibition

PMDD: Treatment for 2 weeks out of the month in the luteal phase

PK

Potent CYP2D6 inhibitor

1A2, 2C19, & 3A4 inhibition 

95% protein bound;

Vd 12-97 L/kg

F= 70;

Classification: Unicyclic, amino-ketone structure

MOA:

NET: 0/+

*modest to moderate NET & DAT

(effect seen in incr. presyn release of NE & DA)

Indication/Clinical Application:

MDD (1st line) 

Smoking cessation

treat sexual affects w/ SSRI use (not consistent data) 

Seasonal Winter Depression

Off-label: ADHD, with other antidepressants to augment MDD therapeutic response

SE and AED's:

agitation, insomnia, anorexia

seizures 

fewer mood symptoms & less wt gain

Contraindications:

Epilepsy (lowers seizure threshold)

MAOis

Therapeutic Considerations: no sex SE

"*binding effects seem less than are typically associated w/ antidepressant"

can be added to SSRI or SNRI for augmentation 

approved in 1997 for smoking cessation (as effective as nicotine patch)

may have some benefit in treating obesity (not robust loss)

PK:

F=70%

T1/2 = 11-14

Active Met T1/2 = 15-25 hr

Vd= 20-30

Protein binding = 84%

Rapidly absorbed

1st pass metabolism; extensively hepatic (2B6* & 2D6 substrate; 2D6 inhibitor)

active met: hydroxybuproprion (being developed as antidepressant, inhibitor of 2D6)

biphasc elimination (1st:1 hr, 2nd phase: ~14 hrs)

metabolism altered by cyclophosphamide

Classification: Tetracyclic

MOA:

H1: +++

5ht2: +

NET: +

Antagonist @ pre-syn Alpha 2 autoreceptors (enhances release of NE & 5HT)

Antagonist @ 5HT2 & 5HT3 postsyn receptors

Potent H1 antagonist

Indication/Clinical Application:

MDD (1st line) - primary

add to SSRI/NRI as augmentation (adjunct to more activating antidepressants)

Other: hypnotic

SE and AED's:least amt

Sedation (H1)

disorientation

tachycardia

Weight gain 

Contraindications:

Therapeutic Considerations:

Introduced 1994

Not associated w/ sexual SEs

Evening dosing

sedative effect may be additive w/ alcohol & benzos (other CNS depressants) 

 Useful in elderly population due to wt gaining & sedative effects 

PK: 

F=50%

T1/2: 20-40 hrs (active met)

Vd=3 - 7 L/kg

Protein Binding: 85%

demethylated, followed by hydroxylation & glucuronide-conjugation

2D6, 3A4, 1A2 substrate

Classification:

5-HT2 Antagonist

MOA:

Inhibition of 5-HT2A receptor; Block SERT weakly (high dose)
Form a low [ ] metabolite (m-cpp) that is an agonist at 5-HT2A,2C & may cause AEs.

A1: ++

5ht2a: ++  in neocortex 

SERT: +

H1: 0/+ (modest)

little effect on NET

Indication/Clinical Application:

treatment of insomnia = primary indication

MDD (w/ or w/o anxiety)

Sedation & hypnosis

 has been used in anxiety

SE & AED's:

Modest α- blockade (orthostatic hypotension) & GI disturbances; 

H1-receptor blockade (sedation), rare priapism

sex effects uncommon (due to 5HT2 rather than on SERT)

Contraindications:

MAOI

Therapeutic Considerations:

"Used principally as a somnorific or hypnotic [off label use] because the higher doses required for antidepressant effects are usually oversedating; Not associated with tolerance or dependence.  

PK:

extensive hepatic metabolism, 

Low concentration active metabolite (m-cpp) w/relatively short half-life."

F = 95% 

T1/2: 3-6 (short half-life)

Vd = 1-3 

Protein binding: 96%

2D6 & 3A4 substrate 

Caution: Use with potent inhibitors of CYP3A4 such as ritonavir or ketoconazole may lead to substantial increases in trazodone levels

Classification:5-HT2 Antagonist

MOA:

5-HT2A antagonist;(post-syn)

Block SERT weakly (high dose)

Form a low [ ] metabolite (m-cpp) that is an agonist at 5-HT2A,2C & may cause AEs

5HT2: ++ -> G-protein coupled in neocortex 

SERT: +

Alpha1: +

NET: 0/+

Indication/Clinical Application:

MDD - primary indication 

anxiety

antipsychotic

PMDD

SE and ADE's:

"Modest α- blockade (orthostatic hypotension)

& GI disturbances; 

Liver failure (Includes rare fatalities & fulminant hepatic failure requiring transplantation; Rate estimated at 1 in 250,000 to 1 in 300,000 patient-years of nefazodone treatment)"

least amt of sexual SEs (due to 5HT2 vs SERT action)

Contraindications:

MAOI, triazolam or carbamazepine

Therapeutic Considerations:

Black Box: hepatic failure 

generic availability

PK:

F = 20%

Well-absorbed,

extensive hepatic metabolism - therefore limited F

short half-life, T = 2-4 hrs

Vd = 0.5 - 1

Protein Binding: 99% 

Low [ ] active metabolite (m-cpp) w/relatively short T1/2 & Hydroxynefazodone

Potent CYP3A4 inhibitor

Can raise the level & Incr. AEs of many 3A4-dependent drugs (Ex: reduction in triazolam dosage by 75% is recommended, 20-fold increase in plasma levels of simvastatin)

Classification: (bicyclic) SNRI

MOA: 

blocks SERT & NET to incr. NE & 5HT activity in synapse

higher affinity for SERT
weaker NET inhibition
SERT: ++ 

NET:+ (at high [ ])

Indication/Clinical Application: 

neuropathies, fibromyalgia, stress urinary incontinence, menopausal vasalmotor symptoms (Hot flashes), possibly enuresis

XR Approved for: MDD, GAD, social anxiety disorder, panic disorder w/ or w/o agoraphobia

SE & ADE's: Common: (dose related)

better SE than imipramine

incr. HR and BP* (esp. w/ IR)(*dose related-seen more than w/ any other SNRI),

insomnia, anxiety, agitation
**HTN
Serious:

cardiac toxcity w/ overdose (more than any other SSRI or SNRI)

Serotonergic effects, D/C syndrome

Contraindications:

MAOi

narrow angle glaucoma

Therapeutic Considerations:

effects similar to impiramine

PK:

F= 45%
plasma t1/2= 8-11 hrs
V= 4-10 L/kg
Fb = 27%

(active met. T1/2 = 9-13)
CYP2D6 extensively mtblized (refer to table 4); daily dosing avail.

CYP2D6 --> desvenlafaxine
**lowest protein bind of all

less safe than SSRIs due to cardiotoxicity

Have lowest protein binding of all antidepressants (27-30%)

excreted 4-8% unchanged in urine

once daily dosing

Metabolites: Desvenlafaxine & Duloxetine

Classification:

bicyclic SNRI

metabolite of Venlafaxine

 MOA:

more balanced inhibitor of SERT & NET

binds to NE & has moderate affinity for DA

Indication/Clinical Application:

Approved for MDD

Under consideration by FDA:

Pain conditions (diabetic neuropathy pain, fibromyalgia - off label use?)

menopausal vasomotor symptoms (hot flashes)

SE & ADE's:

Common: (dose related)

incr. HR & BP (esp. w/ IR), insomnia, anxiety, agitation

Serious:

cardiac toxcity w/ overdose; Serotonergic effects, D/C syndrome

Contraindications:

MAOi

narrow angle glaucoma

Therapeutic Considerations:

Some CYP2D6 inhibition;

similar PK properties to Venlafaxine but less completely metabolized; minor CYP3A4 substrate

45% renal excretion unchanged (conjugated);

once daily dosing avail.

LOW Protein Bound (~30%)

Classification: tricyclic SNRI

MOA: SERT & NET inhibitor ~ equally

binds to NE & has moderate affinity for DA

Indication/Clinical Application:

FDA approved for diabetic neuropathy & fibromyalgia, MDD, GAD

urinary stress incontinence (approved in Europe)

 SE & ADE's:

Common: (dose related), sedation, incr. HR, HTN, anxiety/agitation, insomnia

Serious:

serotonergic effect,

rare hepatotoxicity (duloxetine)- w/ ppl who have had that issue

D/C syndrome

 Contraindications:

MAOi

narrow angle glaucoma

Therapeutic Considerations:

moderate CYP2D6 inhibition to elevate TCA & other substrates;

extensively CYP2D6/1A2 mtblized;

also substrate of CYP 3A4;

daily dosing avail.;

PK: F=50%, plasma t1/2=12-15 hrs, no metabolities, V= 10-14 L/kg, Fb=97%,

well absorbed;

dosing changes needed for hepatic impairments

can be dosed once daily

Classification:MAOI

MOA: 

Hydrazine derivative

(irreversible & nonselective)

Indication/Clinical Application:

 treatment of depression unresponsive to other antidepressants.

MAOI's have historically treated anxiety (PD & SD).

FDA for depression characterized as atypical, nonendogenous, neurotic.

SE and AED's:

more sedating than selegiline or tranylcypromine.

Therapeutic Considerations:

t1/2=11. Potential of overdose.

Classification: MAOI 

MOA:

non hydrazaline

Resembles amphetamine (cause CNS effects) & has a ring hydroxylated & N-acetylated

(irreversible and nonselective (a&b))

Indication/Clinical Application:

FDA: treats MDD w/o melancholia

SE & AED's: 

less sedating than phenelzine

Classification:

irreversible MAOB inhibitor,

inhibits MAO-A at higher doses (becomes non-selective)

Non-hydrazine

Indication/Clinical Application:

Parkingson's disease (low doses)

SE and AED's: 

LESS tyramine toxicity

 Therapeutic Considerations: 

Transdermal selegiline reduces the risk of a tyramine¬induced hypertensive crisis

Sublingual avail. too

allowing patients greater freedom with their diet (& incr. F)

Has amphetamine like (aka active) metabolites

PK

F = 4%

T1/2 = 8-10 hrs

T1/2 active met: 9-10

Vd = 8-10

Fb = 99%

N-demethylated & then hydroxylated

Classification: SNRI

MOA: inhibit SERT & NET (more balanced)

Indication/Clinical Application:

Approved: fibromyalgia;

investigation: variety of pain conditions

SE and AED's:

Serotonin syndrome**, Serotonergic (GI: N, upset, diarrhea; decr. Sex function, Incr. HA, Sleep p-lems, Wt Gain), sedation, incr. HR, HTN, D/C syndrome

Contraindications:

**MAOis,

Narrow-angle Glaucoma

Therapeutic Considerations:

Contains a cyclopropane ring

Not FDA approved for treatment of depression

Classification: irreversible, non-selective MAO inhibition

Indication: 

 FDA approvals: Major depression, esp. w/ anxious mood, panic & phobic symptoms

Therapeutic Considerations:

Hydrazine derivative

Classification: SSRI

MOA:

inhibition of the serotonin transporter (SERT)

SERT: +++

NET:+

AchM:+

Indication/Clinical Application:

panic disorder w/ or w/o AG (dose higher than w/ depression)

 FDA: MDD, OCD, panic disorder w/ or w/o agoraphobia, Social anxiety disorder, GAD, PTSD

SE & ADE's:

Weight gain

Sudden D/C syndrome in some patients (characterized by dizziness, paresthesias and other symptoms)

Contraindications:

Administration with 2D6 substrates such as TCAs (Leads to unpredictable elevations in the tricyclic drug concentration and toxicity)

Therapeutic Considerations:

Strong inhibitor of CYP2D6

not optically active 

PK:

F = 50%

T1/2 = 20-23 hr (shorteR - leads to D/C syndrome)

Vd = 28-31

Fb = 94%

2D6 substrate (AND inhibitor)

Classification: inhibition of the serotonin transporter (SERT)

Indication/Clinical Application: MDD

Sert+++

SE and AED's:gastrointestinal distress, somnolence 

: Therapeutic Considerations:exist as isomers (Formulated in the racemic forms); Only modest CYP interactions ( 2C19 partial sub and 3A4); Relatively free of pharmacokinetic interactions

f=80%

t1/2=33-38h

vd=15l/kg

fb=80%

Classification: SSRI

MOA:

inhibition of the serotonin reuptake transporter (SERT)

SERT:+++

Indication/Clinical Application: 

MDD, GAD (FDA)

SE & ADE's:

nothing specific to drug (only general to SSRI):

Therapeutic Considerations:

Relatively free of PK interactions (modest CYP interaction)

S-enantiomer of Citalopram

PK:

F-80%

T1/2 = 27-32%

Vd = 12-15%

Fb = 80%

3A4 substrate

Classification:SSRI

MOA:

inhibition of the serotonin reuptake transporter (SERT)

 SERT: +++

Indication/Clinical Application:

PMDD,

MDD,

acute & maintenance OCD,

PD w/ or w/out agoraphobia PTSD,

social anxiety

SE and AED's:

withdrawal symptoms (dizziness, parasthesia - skin burning/tingling) if D/C w/o tapering. - begins 1-2 days w/o stopping drugs and lasts for 1 week longer

Therapeutic Considerations:

active metabolite long T1/2, although still a warning if pt discontinues med for withdrawal symptoms.  

2C19 & 3A4 inhibitor

exists as isomer (racemate formulation)

modest CYP interactions

PK:

F = 45%

T1/2 = 22-27 hr

T 1/2 met: 62-104 hr

Vd = 20 L/kg

Fb = 98%

Classification: SSRI

MOA:

inhibition of the serotonin reuptake transporter (SERT)

 SERT: +++

Indication/Clinical Application:

OCD

Contraindications:

MAOi,

narrow angle glaucoma,

bupropion (3A4 substrate)

Therapeutic Considerations:

CYP3A4 inhibitor, & 2C19 & 1A2 inhibitor

not optically active

NOT APPROVED FOR DEPRESSION!!!!

PK:

F = 90%

T1/2 = 14-18 hrs

T1/2 active met: = 14-16

Vd = 25 L/kg

Fb = 80%

Classification:typical antipsychotic

MOA:D2 block

Indication/Clinical Application:Uncontrollable hiccups!  and schizophrenic symptoms

SE and AED's: EPS, sedation, hypotension.  anti SLUD, Weight gain - greatest liklihood among typicals, deposits in the cornea and lens which accentuate aging.  Cholestatic jaundice, skin reactions and photo sensitivity too.

Therapeutic Considerations:blocks: alpha1=5-HT2a>D2>D1.  Low potency.  Medium EPS toxicity (D2).  Highly sedative (H1).  High hypotensive agent (alpha1).  M1 block too - avoid in elderly.  Seizure risk.  Very broad dosing range!   CYP 2D6 inhibitor.

Classification: typical antipsychotic

MOA: D2 block

Indication/Clinical Application:schizophrenia

SE and AED's: sedation (H1), retinal deposits causing "browning" of vision

Therapeutic Considerations:black box warning for torsade/fatal arrhythmia.  Inhibits Na channel at high doses!  Unlike other antipsychotics - not an antiemetic.  2D6 inhibitor

Classification:Typical Anti-pyschotic

piperazine

MOA: potent D2 blockade

Indication/Clinical Application:Schizophrenia

SE and AED's:Causes EPS effects such as akathisia, dystonia, and Parkinsonism; somnolence; xerostomia (dry mouth); impotency, infertilitiy

 Therapeutic Considerations:very potent and very selective in pharmacologic effects

Classification:Typical Anti-pyschotic

MOA: potent D2 blockade

Indication/Clinical Application:schizophrenia and the manic phases of bipolar disorder

SE and AED's: Causes EPS effects such as akathisia, dystonia, and Parkinsonism; somnolence; xerostomia (dry mouth); impotency, infertilitiy

 Therapeutic Considerations:very potent and very selective in pharmacologic effects. Inhibit 2d6

Classification:Typical Anti-pyschotic

MOA:potent D2 blockade

Indication/Clinical Application: schizophrenia and the manic phases of bipolar disorder, agitation, and dementia

SE and AED's: Causes high EPS effects such as akathisia, dystonia, parkinsonism, and rabbit syndrome

Therapeutic Considerations:long acting injectable (depot) high clinical potency

Classification: thioxanthene derivative (Typical)

MOA: D2 receptor blockade

Indication/Clinical Application: Schizophrenia

SE and AED's: Medium extrapyramidal toxicity (Parkinson's syndrome, Akathisia, acute dystonic rxns), sedation, & hypotensive actions; NMS, Tardive Dyskinesia

 Therapeutic Considerations:High Potency

Classification:Typical: Butyrophenone Derivative

MOA: Potent D2 Blockade: D2 > Alpha1 > D4; 5HT2A > D1 > H1

Indication/Clinical Application: Schizophrenia

SE and AED's: Movement disorders, Incr. prolactin, Low sedation, very low  hypotensive actions; Very High EPS, Torsade/fatal arrythmias; Neuroleptic Malignant Syndrome; Tardive Dyskinesia

 Therapeutic Considerations:Most widely used typical; Long-acting injectable form; *Tends to be more potent, have fewer autonomic effects, & greater Eps; Black box warning (torsade/fatal arrhythmias)

Classification:typical antipsychotic diphenylbutylpiperidine derivative

 Indication/Clinical Application:tourette's

SE and AED's: Black box: torsade/fatal arrhythmias, EPS side effects

Therapeutic Considerations:compared to phenothiazines/butyrophonones and congeners the butyophenone derivatives are more potent, have autonomic effects, tend to have greater EPS

Classification: atypical antipsychotic

MOA:D4=alpha1>5-HT2A>D2=D1, M1 blockade in the central and peripheral nervous system, M4 agonist

Indication/Clinical Application:schizophrenia, refractory disease in suicidal patients

SE and AED's:sedative action, Orthostatic hypotensive actions(alpha 1), very low EPS, constipation(strong), sialorrhea(m4), weight gain(strong), displipidemia(strong), hyperglycemia (Strong). myocarditis (maybe), 1% develop agranulocytosis

 Therapeutic Considerations:lowest risk of hyperprolactinemia, should be considered a second line drug, all schizophrenic patient who have made life-threatening suicide attempts should be seriously evaluated for switching to clozapine, has unique effectiveness in refractory disease, has a seizure risk (3-5%). agranulocytosis: greatest risk in first 6 mo (peak 2-3 mo), serious/potentially fatal, DC (don't rechallenge), appears to reverse after DC, must have weekly blood counts for first 6mo, every 2w in months 6-12, then every 4 weeks. mixed results with add on of strong D2 antagonist with clozaine. changes in smoking behavior are problematic in clozapine treated pnts. Never discontinue unless side effects are medical emergencies. discovered in 1959- led to atypical antipsychotics

Classification:Atypical

Thienobenzodiazepine

 MOA: Antagonist

5HT2A>H1>D4>D2>α1>D1

some alpha 2 antagonism

Indication/Clinical Application: monotherapy for biopolar mania maintainence

w/ Fluoxetine, approved for biopolar depression

SE and AED's:moderate sedation, low hypotension, major wt gain, major dyslipidemia, hyperglycemia (greatest risk) , suicidal thoughts?? related to higher doses? (slide 60), tolerance, anticholinergic, rebound insomnia/sleep distrubance, low EPS

Therapeutic Considerations:should be used as 2nd line drugs (at high doses, might treat refractory)

high potency

olanzapine/fluoxetine combo approved for bipolar depression

Classification:Atypical 

Dibenzothiazepine

 MOA: Antagonist 

H1>α1>M1,3>D2>5-­‐HT2A

some alpha 2 antagonism

you are not quiet when you laugh (HA)

Indication/Clinical Application: schizophrenia, MDD, bipolar

SE and AED's:moderate sedation, moderate to low hypotension, tolerance, rebound insomnia/sleep distrubance, some dyslipidemia and hyperglycemia, QTc prolongation, low EPS

 Therapeutic Considerations:low potency

Classification:Atypical Antipsychotic

MOA:5-HT2A > D2 receptor antagonism

Indication/Clinical Application: *Special: FDA approved for irritability in autism; Injectable risperidone approved as maintenance for bipolar 1*; AAP- Primary indiction: Schizophrenia (except catatonic form); also used in acute mania in Bipolar 1 and adjunct for major depression; Substance-induced psychosis, Tourette's, delirium and dementia (warning of inc mortality for dementia though), adjunct in anxiety disorders (OCD, PTSD);

SE and AED's:High clinical potency, low EPS, sedation, and hypotension.

Unlike most atypicals, risk of hyperprolactinemia!  (Which can cause amenorrhea-galactorrhea syndrome & infertility and may lead to osteoporosis in women; loss of libido, impotency, & infertility in men); Less dyslipidemia & hyperglycemia'

 Contraindications:Be careful with peds (sensitive to EPS & wt gain; hyperprolactinemia- some tolerance occurs) and elderly (sensitive to EPS, TD, orthostatis, sedation, and anti-cholinergic effects; potential of drug/drug interactions; risk for cerebrovascular events and all-cause mortality with dementia)

Therapeutic Considerations:Risperidone is rapidly converted to 9-hydroxyrisperidone (Paliperidone) in vivo in most patients except for about 10% who are poor metabolizers.

Classification:Atypical Antipsychotic; Active metabolite of Risperidone

MOA: 5-HT2A > D2 receptor antagonism

Indication/Clinical Application: AAP- Primary indiction: Schizophrenia (except catatonic form); also used in acute mania in Bipolar 1 and adjunct for major depression; Substance-induced psychosis, Tourette's, delirium and dementia (warning of inc mortality for dementia though), adjunct in anxiety disorders (OCD, PTSD)

SE and AED's:High clinical potency, low EPS, sedation, and hypotension.

Unlike most atypicals, risk of hyperprolactinemia!  (Which can cause amenorrhea-galactorrhea syndrome & infertility and may lead to osteoporosis in women; loss of libido, impotency, & infertility in men); Less dyslipidemia & hyperglycemia

 Contraindications:Be careful with peds (sensitive to EPS & wt gain; hyperprolactinemia- some tolerance occurs) and elderly (sensitive to EPS, TD, orthostatis, sedation, and anti-cholinergic effects; potential of drug/drug interactions; risk for cerebrovascular events and all-cause mortality with dementia)

Therapeutic Considerations:Does NOT undergo extensive CYP metabolism and conjugation

Classification:Atypical Antipsychotic

MOA:5-HT2A > D2 receptor antagonism

Indication/Clinical Application: Acute mania in Bipolar Disorder

SE and AED's: Weight gain/metabolic changes, Prolactin elevation, Sedation, Orthostatic hypotension, QTc prolongation, EPS/TD; oral hypoesthesia

 Therapeutic Considerations:New: SUBLINGUAL (only) (do not eat or drink w/in 10 min. of admin.) - poor GI absorption. *Type 1 Hypersensitivity Reactions. Not extensive metab by cy and then conjugated. 

Classification:Atypical Antipsychotic

MOA:5-HT2A > D2 receptor antagonism, D2; 5-HT1A, 2A, 2C,1D; Alpha1

Indication/Clinical Application: Acute mania in Bipolar Disorder

SE and AED's: Prolactin elevation, Sedation, Orthostatic hypotension, QTc prolongation, EPS/TD

Therapeutic Considerations:Avail as: oral capsule, short acting IM injection. Potential for Drug-Drug: Metabolized via CYP450

Classification: Atypical Antipsychotic

MOA:D2 partial agonist; Aripiprazole

gains therapeutic efficacy through 5-­‐HT2A

antagonism and maybe 5-­‐HT1A partial

agonism

 d2= ht2a>d4>alpha 1= h1>>d1

 Indication/Clinical Application:schizophrenia

SE and AED's:Very low EPS, sedative, and hyptensive action, Lowest risk of hyperprolactemia

 Therapeutic Considerations: approved for monotherapy for maintenance in BP disorder

Classification:Atypical but sometimes classified as Typical Antipsychotic

MOA:inhibits 5-­‐HT2A

and

D2

Classification:Atypical Antipsychotic

MOA:-Stronger inverse agonist blockade at 5HT-2a receptor               -Weaker D2 receptor antagonism

Indication/Clinical Application: Schizophrenia (not catatonic form); Psychotic bipolar disorder 1; Major depression adjuncts; schizoaffective disorders; substance-induced psychosis; tourette's syndrome (tics); psychotic symptoms of delirium and dementia

SE and AED's: -Weight gain, hyperglycemia warning          -EEG shifts: slow them & increase their synchronization; Q-T prolongation               -Respiratory Depression fatality in combo w/ other medications

Classification:Phenothiazines used primary for other indications

MOA:DA antagonism in Chemoreceptor trigger zone

Indication/Clinical Application:primarily an anti-emetic

Classification: Phenothiazines Antipsych

 Indication/Clinical Application:Used with fentanyl for neuroleptanesthesia

Classification:Butyrophenone Antisych

Indication/Clinical Application:Neuroleptanesthesia.   Also to decrease post-operative nausea and vomiting.

Classification: Benzodiazepine

MOA:-

Bind to specific BZ site of the GABAa receptor b/w alpha 1 & gamma 2 subunits to facilitate an increase in the frequency of Cl- channel opening, hyperpolarization

 Indication/Clinical Application:

seizure disorders

 anxiety

 Therapeutic Considerations: -

Prodrug: is converted to active Nordiazepam by stomach acid hydrolysis;

-Long half-life: 48 hrs

-Hepatic metabolism: N-dealkylation & aliphatic hydroxylation

Active metabolite rate of absorption is faster than other commonly used benzos

NOT biologically active

Route of admin:

oral

Classification: Benzodiazepine

 MOA:

-Bind to specific BZ site of the GABAa receptor b/w alpha 1 & gamma 2 subunits to facilitate anhyperpolarization

 Indication/Clinical Application: 

seizure disorders; adjunct in acute mania; movment disorders

Therapeutic Considerations:

More sedating

-Tolerance develops to anticonvulsant effects;

-Long half-life: 20-40 hrs

-Metabolised by reduction of 7-NO2 group to inactive amine then acetylated

ORAL route of admin.

Classification: Benzodiazepine

Indication/Clinical Application: 

Acute anxiety states, panic attacks, generalized anxiety disorder, insomnia & other sleep disorders, relaxation of skeletal muscule, anesthesia (adjunct), and seizure disorders

Therapeutic Considerations:Oral, used in insomnia, active metabolites which may accumulate with chronic use, t1/2 = 39 hrs

Daytime Sedation more common (due to active metabolites)

Classification: Benzodiazepine

Indication/Clinical Application: Insomnia

SE and AED's: Daytime anxiety when used to treat sleep disorders.

 Contraindications: Additive CNS depression with ethanol and many other drugs

 Therapeutic Considerations:Oral, extremely rapid absorption due to lipophilicity (and rapid onset of CNS effects), used in insomnia, rapidly inactivated (undergoes alpha-hydroxylation, metabolites have short half life due to rapid conjugation, and forms inactive glucoronides); May cause disturbing daytime side effects (daytime anxiety when used to treat sleep disorders)

t1/2: 2-3hrs

Contains triazole ring at 1,2-position
REM rebound with abrupt cessation (especially due to short duration of action and when at high doses)

Favors its use as a hypnotic rather than a sedative drug

ROUTE: Oral

PK: Affected by inhibitors/inducters of hepatic P450s

Classification: Barbiturate GABA A receptor agonist

Indication/Clinical Application:insomnia, preoperative sedation, emergency management of seizures

 SE and AED's:

 Contraindications: 

Therapeutic Considerations:IM, IV (only the sodium salt form given parenterally)

t1/2: 10-40 hrs,

Route: IM, IV

Classification: Barbiturate GABA A receptor agonist

 Indication/Clinical Application: insomnia, preoperative sedation

Therapeutic Considerations:redistribution shortens duration of action of single dose to 8 hrs

t1/2: 35-50 hr

Route: Oral

Classification: Barbiturate GABA A receptor agonist

 Indication/Clinical Application: seizure disorders, daytime sedation

Therapeutic Considerations:2nd line anticonvulsant

t1/2: 10-70 hrs

Route: Oral

Classification: Barbituate

 Indication/Clinical Application: insomnia, preoperative sedation, emergency management of seizures

Therapeutic Considerations:elimination half lives about 18-48hrs (vary), only sodium salt administered parentally, even though older generation it is still used.

Routes: Oral, IM, IV, Rectal

Classification: barbituate

MOA:Bind to specific GABAA receptor subunits at CNS neuronal synapses facilitating GABA-mediated chloride ion channel opening duration

Enhance membrane hyperpolarization

 Indication/Clinical Application: seizure disorders, status epilepticus, daytime sedation, effective in treatment of generalized tonic-clonic seizures, since it is long-acting- might help with withdrawal from alcohol or other sedative hypnotics (admin in taper down)

SE and AED's:

Steeper dose-response than benzodiazepines

 Contraindications:Additive CNS depression with ethanol and many other drugs

Induction of hepatic drug-metabolizing enzymes

 Therapeutic Considerations:half life= 4-5 days in humans, multiple dosing with this can lead to cumulative effects. excreted unchanged in the urine abour 20 to 30% in humans. Elimination rate can be increased significantly by alkalinization of the urine. Phenobarbital is a weak acid with a Pka of 7.4, increased ionization at alkaline PH. very likely to cause induction-may result in an increase in their hepatic metabolism as well as that of other drugs. Potential mechanism underlying drug interactions.

Pharmacokinetics: Half-lives from 4 to 60 hours

Oral activity, IM, IV
Hepatic metabolism
Phenobarbital 20% renal elimination
Toxicity: Extensions of CNS depressant effects dependence liability greater than benzodiazepines

Classification: barbituate

MOA: Bind to specific GABAA receptor subunits at CNS neuronal synapses facilitating GABA-mediated chloride ion channel opening duration

Enhance membrane hyperpolarization

Indication/Clinical Application:insomnia, preoperative sedation

 Therapeutic Considerations
Only sodium salt is available, even older still used,Incidence of drug-related deaths is 11.6 deaths per million capsules of secobarbitalRoute: Oral

Pharmacokinetics: Half-lives from 18-48 (variable) hours
Hepatic metabolism
Phenobarbital 20% renal elimination

Classification:hypnotic, imidazopyridine, new hypnotic

 MOA: Bind GABAA receptor; Bind GABAA-receptor isoforms that contain α1 subunits(BNZ)● Receptor functions as a chloride ion channelActivated by the inhibitory neurotransmitter GABA

Indication/Clinical Application: sleep disorders. has efficacies similar to those benzos in the anagement of sleep disorders.

SE and AED's:amnesia, somnolence; category C, REM rebound @ higher doses. tolernace with extended use.Abrupt cessation= withdrawal (less intense than benzos). Causes more amnesia or day-after solmnolence than the other newer drugs

 Therapeutic Considerations: Flumazenil can resverse the effects of drug. Decreases REM sleep, minimal effect on slow wave sleep Lacks anticonvulsant/muscle relaxant activity.Less likely than the bnz to change sleep patterns (little known about the clinical impact of these effects on sleep architecture). generally more preferred than benzo. One of the most frequntly prescribed hypnotic drugs in the United States. Available in a biphasic release formulation (provide sustained drug levels for sleep maintenance) . Fwe reports of tolerance when used for less than 4 weeks compared to benzos. Withdrawal symptoms minimal

PK:

Rapidly oxidized and hydroxylated to inactive metabolites hepatic cytochrome P450s (Includes CYP3A4 isozyme); Clearance decreases in elderly patients, oral administration- reached peak of plasma levels in 1.6hours. no active metabolites. Tmax= 1-3hrs. t1/2= 1.5-3.5 hrs.

Classification: hypnotic

MOA:Melatonin receptor agonist at MT1 and MT2.(melatonin- maintains circadian rhythms underlying sleep-wake cycle.

 Indication/Clinical Application: patients who have difficulty in falling asleep. Reduces the latency of persistant sleep.

SE and AED's:Dizziness, somnolence and fatigue; Endocrine changes (Decreases in testosterone and increases in prolactin); category C

 Contraindications: inhibitors of CYP1A2 Examples: ciprofloxacin, fluvoxamine, tacrine and zileuton, inhibitors of CYP2C9 (Example: fluconazole),liver dysfunction

 Therapeutic Considerations:newer hypnotic drug. No directed effects on GABA NT in the CNS. No effects on sleep architecture. Min rebound insomnia/significant withdrawal symptoms. Not a controlled drug. Preg Cat C

PK:

Rarpidly absorbed after oral administration

Undergoes extensive first-pass metabolism

b. Forms an active metabolite (Longer half-life (2–5 hours) than the parent drug)
c. Metabolized by mainly by CYP1A2 & CYP2C9; Rifampin (induc) markedly reduces the plasma levels of both ramelteon and its active metabolite; Fluvoxamine inhibits metabolism

Classification:anxiolytic agent

 MOA:May be by acting as a partial agonist at brain 5-HT1A receptors; Also has affinity for brain dopamine D2 receptors. no Gaba effect

 Indication/Clinical Application: Generalized anxiety states (Less effective in panic disorders)

SE and AED's: Nonspecific chest pain, tachycardia, palpitations and dizziness; Nervousness, tinnitus, gastrointestinal distress and paresthesias; Dose-dependent pupillary constriction; Blood pressure may be significantly elevated in patients receiving MAO inhibitors

 Therapeutic Considerations:Different actions from conventional sed/hyps. no  marked sed/hyp/ or euphori effect. Not anticonvuls/muscle relax prop. No rebound anx/withdrawal signs on arbupt discontinuance.Not effective in blocking the acute withdrawal syndrome resulting from abruot cessation (benzo or other sedative hypnotics). Has min abuse liability. Anxiolytic effects of buspirone may take >week to become established (Unsuitable for management of acute anxiety states); Major metab=1-(2-pyrimidyl)-piperazine (1-PP) (has alpha 2 adrenoceptor block action, enters the CNS to reacher higher levels than parrent drug, role unknown) Less psychomotor impairment than benzos, doesn't affect driving skill. Doesn't potientiate effects of conventional sedative-hypnotic drugs, ethanol/TCA's. Elderly pnts do not appear to be more sensitve to its actions. Preg cat B

PK:

Rapid absorb orally. Hydroxylation and dealkylation rxns forming several active metabolites. Rifampin decreases the half-life of buspirone; Inhibitors of CYP3A4

● Examples: erythromycin, ketoconazole, grapefruit juice and nefazodone
● Can markedly increase its plasma levels

t1/2= 2 to 4 hours. Liver dysfunction may slow clearance.

Classification: sedative-hypnotic, carbamate

MOA: exert inhibitory effects on polysynaptic reflexes and internuncial transmission. @ high doses may depress transmission at the skeletal NM junction.

Indication: claims for usefulness for relaxing contracted coluntary muscle in Musclespasm. Approved fro the treatment of anxiety disorders, but widely used as a nighttime sedative

SE:, overdosage can cause severe hypotension, respiratory depression, and death.Higher potential for abuse, less selective anti-anxiety effects. Can cause widespread depression of the CNS, cannot produce anesthesia. Large doses can cause severe fatal respiratory depression, hypotension, shock, and heart failure. Usual sedative doses
- Drowsiness and ataxia
● Larger doses
- Impairment of learning and motor coordination
- Prolongation of reaction time
● Enhances the CNS depression produced by other drugs

 Therapeutic Considerations:rarely used, likely to induce metabolism enzymes- may result in an increase in their hepatic metabolism of themselves and other drugs. Distinctive chemical structure. Practically equvalent to barbituates in their phamracological effects. Doesn't resemble barbituates. T1/2- 6-17h, oral admin. Acts kinda like a Benzo. Causes little impairment of locomotor activity. Appear to have mild analgesic effects in pnts with muscoskeletal pain (enhances the analgeics effects of other drugs) Abuse of meprobamate= Has continued despite a substantial decrease in the clinical use.Evidence for general efficacy without accompanying sedation is lacking

PK:Well absorbed when administered orally
● Intoxication with meprobamate is through formation of gastric bezoars
- Treatment may require endoscopy with mechanical removal of the bezoar
● Most of the drug is metabolized in the liver
● Half-life of meprobamate may be prolonged during its chronic administration Parent dug= Carisprodol

Classification:sedative-hypnotic

MOA:Trichloroethanol exerts barbiturate-like effects on GABAA-receptor channels
d. Trichloroethanol is conjugated mainly with glucuronic acid
● Product urochloralic acid is excreted mostly into the urine

Indication:Used in the past for the production of sedation in children
- Undergoing diagnostic, dental or other uncomfortable procedures

SE:chronic use may cause hepatic damage; withdrawal syndrome is severe-( May result in delirium and seizures
High frequency of death when untreated).Irritating to the skin and mucous membranes
- Unpleasant taste, epigastric distress, nausea and occasional vomiting
- Drug should sufficiently diluted
● CNS effects(Lightheadedness, malaise, ataxia and nightmares)
● Acute poisoning
- May cause jaundice
- Parenchymatous renal injury may occur

 Therapeutic Considerations:rarely used, Distinctive chemical structure ● Practically equivalent to barbiturates in their pharmacologic effects,Oral, rectal admin.

PK:● t1/2:5–10*Rapidly converted by hepatic alcohol dehydrogenase to trichloroethanol, which is largely responsible for the effects of chloral hydrate
● Significant amounts of chloral hydrate are not found in the blood

Classification:

Competitive Benzodiazepine Antagonist

MOA:

high affinity for benzo binding site on GABAa receptor

Indication/Clinical Application:

Reverses/Blocks sedative actions of BZs, Eszopiclone, Zaleplon & Zolpidem;

Approved: Reversing the CNS depressant effects of BZ overdose; Hasten recovery following use of BZs in anesthetic & diagnostic procedures

SE and AED's:

(Toxicity): Agitation, Confusion, Dizziness & Nausea; Abstinence Syndrome (insomnia, restlessness, tremulousness, hallucinations & in the extreme, potentially fatal tonic-clonic convulsions) ; Seizures & arrhythmias in pts who have taken BZs w/ TCAs. Develope BZ dependance. Risk the pircipitation of withdrawl syndrome in BZ users.

Contraindications: none specific known

Therapeutic Considerations:

1,4-benzo derivative; Antagonism of BZ-induced respiratory depression is less predictable*

IV formulation: acts rapidly, short T1/2 (0.7-1.3 hrs), rapid hepatic CL (all BZs have a longer DoA) --> Often have to re-dose because sedation commonly recurs due to short t1/2, All BNZD have a longer duratin of action than flumazenil. Does not help in reversal of the non BNZD/derivative resp depression. Must monitor resp function when using.

Classification: Pyrazolopyrimidine; Benzodiazepine receptor Agonist "Newer Hypnotic"

MOA:

Binds selectively at the BZ sites that contain an alpha1 subunit of the GABA receptor,. 

Indication/Clinical Application:

useful in the management of patients who awaken early in the sleep pattern

SE and AED's:

Extensions of CNS depressant effects, Minimal withdrawal symptoms. Rebound insomnia occures if used @ higher dose

Contraindications:

Additive CNS depression w/ EhOH & other drugs; Pregnancy Category C

Therapeutic Considerations:

Efficacy similar to BZs in managing sleep; Rapid onset of activity; Modest day-after psychomotor depression w/ few amnestic effects (< than Zolpidem or BZs); Little effect on total sleep time, NREM, or REM sleep; Rebound Insomnia occurs if used at higher doses; Minimal tolerance observed over a 5-week period; Abrupt cessation may result in withdrawal symptoms (< than seen w/ BZs); Less likely than BZs to change sleep patterns (little known about the clinical impact of these effect on sleep architechture;

(lacks anticonvulsant and muscle relaxation activity; Sedative actions reversed by Flumazenil) Causes less amneia od day after somnolence than zolpidem or benzodiazepines  Fewer reports of tolerance/withdrawal when used for less than 4 weeks 

PK

Metabolized via hepatic aldehyde oxidase (DH) & partly 3A4 to INactive metabolites; Both Met. paths inhibited by Cimetidine (= more increase peak plasma); Reduce dose in ppl w/ hepatic impairment & elderly; T1/2 ~ 1hr; Tmax < 1hr. Doesn't antagonize action of barbituates, meprobamate or ethanol. Acts rapidly with short half life

Classification:

Benzodiazepine receptor Agonist ("Newer Hypnotic")

MOA:

Binds selectively at the BZ sites that contain an alpha1 subunit

Indication/Clinical Application:

Sleep Disorders: Hypnotic: Increases total sleep time (mainly via incr. in stage 2, not REM). Rapid onsent, and less carry over sedation.

SE and AED's:

Fewer cases of tolerance W/I 4 weeks. Minimal withdrawl symptoms.

Contraindications:

Pregnancy Category C

Therapeutic Considerations:

Cyclopyrrolone, (S) enantiomer of zopiclone; Available outside US since 1989;  not REM. Loe dosage has little effect on sleep patterns. Highest dosage decreases REM sleep. Withdrawl with abrupt cessation however less intesne than that with benzos. Less likely than a Benzo to change sleep paterns. Little is know about the impact on sleep architecture. Preferred drug out of newer class-I guess? Efficacy similar to Benzo in sleep managment. Apparently less amnesia and day after solomance compared to BZ/zopidem.

PK:

Absorbed rapidly following oral admin.; metabolized by CYP3A4, forms inactive N-oxide derivative & weakly active desmethyleszopiclone; T1/2 ~ 6hrs (Prolonged in elderly, in presence of 3A4 inhibitors like ketoconazole, decr. by 3A4 inducers, rifampin); Tmax 1hr

Classification: SNRIs

MOA:

moderately selective block for SERT & NET

(Acute incr. in Serotonergic & NE in synapse)

Indication/Clinical Application:

Depression

Anxiety 

Panic disorder (w/ or w/o agoraphobia)

SE and AED's:

Serotonergic effects

Sedation

Incr. HR

HTN

D/C syndrome

Contraindications:

MAOis

Classification:MAOi

MOA: inhibits MAO

Indication/Clinical Application:

depression

SE and AED's:

orthostatic hypotension

wt gain

sex dysfunction

anorgasmia 

sedation

confusion

CNS activation

insomnia

restlessness (amphetamine-like effects)

D/C syndrome

systemic tyramine toxicity (HTive crisis)

can precipitate manic or hypomanic episodes in bipolar patients

Contraindications:

Serotonergic drugs

fermented food 

Therapeutic Considerations:

extensive drug-drug interactions

PK:

well absorbed

heavily metabolized

inhibit GI MAOs

very slow elimination 

MOA:

binds BZ on GABAa in CNS

 --> Cl incr. (hyperpolarization) (incr. frequency of Cl opening)

Indication/Clinical Application:

acute anxiety states

panic attacks

GAD

insomnia/other sleep disorders

relaxation of skeletal muscle

anesthesia (adjunct)

seizure

SE and AED's:

dose-dependent depressant effects on CNS

amnesia

hypnosis

anesthesia

coma

respiratory depression

sedation & relief anxiety

Contraindications:

Additive CNS depression w/ EtOH & other drugs

PK:

T1/2: 2-40 hours 

oral activity

hepatic metabolism

toxicity extensions of CNS depressant effects & dependence liability

Classification: Barbs SMARBS

MOA:

bind to specific GABAa subunits in CNS

 leads to incr. duration of Cl channel opening --> hyperpolarization

Effects:

dose dependent depressive effects on CNS

sedation & relief of anxiety

amnesia

hypnosis

anesthesia

coma

respiratory depression

steaper dose response than benzos

Toxicity:

extensions of CNS depressant effects

dependence liability greater than benzos

Contraindications:

 Additive CnS depression w/ EtOH & other drugs

induction of hepatic drug metabolizing enzymes

PK:

T1/2 : 4-60 hrs

oral activity

hepatic metabolism

MOA:

bind selectively to a subgroup of GABAa receptors

(binds BZ subunits w/ alpha1) (to enhance hyperpolarization)

Indication/Clinical Application:

sleep disorders (esp. w/ difficulty falling asleep)

Toxicity:

extension of cNS depressant effect

dependence liability

Interactions:

additive CNS depression w/ EtOH and other drugs

Therapeutic Consideration:

rapid onset of hypnosis

few amnesic affects or psychomotor depression (day after) or somnolence

PK:

oral activity

short T1/2

CYP substrate

Classification: benzo

Indication/Clinical Application:

anxiety

agoraphobic & panic disorders (more selective in these condition than other benzos)

SE and AED's:

withdrawal symptoms may be especially severe. More toxic in overdose (polypharmacy)

Therapeutic Considerations:

addition of triazole ring at 1,2 position

undergoes alpha hydroxylation

PK:

T1/2 = 12 hrs

metabolites have short T1/2 due to rapid conjugation

forms active glucourinides

ORAL form

Classification:

benzos

Indication/Clinical Application:

Anxiety disorders

Management of EtOH withdrawal

Anesthetic premedication

Therapeutic Considerations:

Routes of Admin: oral, IM, IV

Long acting & self-tapering (due to active met)

alleviate withdrawal symptoms of shorter acting drugs (including EtOH)

PK:

T1/2 = 10 +/- 3.4 hrsactive metabolite: desmethyldiazepam (long T1/2 > 40 hrs)

Classification:Benzo

Indication/Clinical Application:Insomnia,

SE and AED's:Similar to triazolam

Therapeutic Considerations:Contains a triazolo ring

 Route: Oral

PK: Short t1/2 metabolized into glucuronides and therefor less sedating effect.  t1/2: 10 - 24 hours

Classification: Benzo

Indication/Clinical Application: Anxiety Disorders, Status Epilepticus/seizures, anasthetic premedication (adjunct, large doses).  Skeletal Muscle  relaxant without sedation.

Contraindications: Rapid absorption compared to other BNZD. .

Therapeutic Considerations:Prototypical benzo, IV for anasthesia in combination with other medications, May contribute to post anasthesia, respiration depression - probably related to long t1/2 and active metabolites. Long acting drug and used for withrdrawl of shorter acting drugs such as ETOH. Hard to die from this medication

 Routes: Oral, IM, IV, Rectal

PK: Metabolism affected by P450 altering drug, t1/2 is 43 +- 13hrsActive metabolite is Desmethyldiazepam with a t1/2 of 40hrs

Classification:

Indication/Clinical Application: Insomnia

SE and AED's:Daytime sedation.

Therapeutic Considerations:active metabolites accumulate with chronic use.

 Route: Oral

PK: t1/2: 74 +-24hrs.

Classification:benzo

Indication/Clinical Application:Preanasthetic, intraoperative,

Therapeutic Considerations:used in IV for anasthesia in combination with other medications, given in large doses in adjuct for anasthesia. May contribute to post anasthesia respiratory depression.

Route: IV, IM

PK: effected by P450 enzymes and therefore watch out for induces/inhibitors. rapidly inactivated: t1/2 1.9+-0.6hrs.

Classification:Benzo

Indication/Clinical Application:Anxiety disorders, pre-anasthetic, managment of seizures.

SE and AED's: Daytime sedation

Therapeutic Considerations: IV for anasthesia in combinatino with other products. Given in large doses may contribute to post anasthetic respiratory depression, most likely related to long t1/2 and active metabolites. parenteral used for ETOH withdrawl.

Route: Oral, IM, IV

PK:Short t1/2, metabolized into inactive gluceronides and therefore less sedation. Metabolized soley by congugation. T1/2: 14+-5hrs

Classification:Benzo

Indication/Clinical Application: Anxiety,

Therapeutic Considerations: less sedation.

Route: Oral

PK: Short t1/2 and make into an inactive gluceronide. Metabolized soley by conjugation. t1/2: 8+-2.4hrs.

Classification:Benzo

Indication/Clinical Application: Insomnia

SE and AED's: Daytime sedation more common due to active metabolites.

Therapeutic Considerations: active metabolites accumulate with chronic use

Route: Oral

PK: t1/2: 39

Classification:Benzo

Indication/Clinical Application: Insomnia

Route: Oral

PK: Metabolised by conjucation. t1/2: 11+-6hrs

Classification:

Indication:Teatment of withdrawal reactions
 Especially delirium tremens in hospitalized patients
● Treatment of other psychiatric states characterized by excitement
● Has been used for the treatment of convulsions including status epilepticus in children

SE:toxicities include acidosis, nephrosis, gastritis and fatty changes in the liver and kidney
- Can lead to toxic hepatitis

Contraindication:

Therapeutic Consideration:Oral, rectal admin.Orally it is irritating to the throat and stomach
● Rectally the drug is diluted with olive oil. Oral:Sleep usually ensues in 10 to 15 minutes after hypnotic doses

PK:eliminated by hepatic metabolism (75%) and exhalation (25%),Oral:Absorbed rapidly and distributed widely.70% to 80% of a dose is metabolized in the liver.Converted to carbon dioxide and water.- Most of the remainder is exhaled
◦ Produces a strong characteristic smell to the breath

T1/2:4–10