Amitriptyline

Hydrochloride
Tablets 10,25 mg
CONTRAIND concomitantly with
ICATIONS a MAO inhibiting,
Hyperpyretic crises,
severe convulsions,
acute recovery phase
following myocardial
infarction, presence of
acute congestive heart
failure

Prophylactic Amitriptyline 25150 mg Nortriptyline 10150

Migraine at bedtime mg at bedtime
Therapies
Posttraumati 2550 mg per day
c Stress
Disorder
Narcolepsy 50200 mg/d
(cataplexy)
Smoking Second-line Titrate up
Cessation to 75100 mg orally
daily 612 months Dry
mouth, blurred vision,
and constipation are
dose-dependent
adverse
effects.***FDA not
approved
Urinary 25100 mg at bedtime
Incontinence
Contraindicat -cisapride; may cause Concomitant use with
ions QT interval prolongation linezolid or IV
and increase the risk of methylene blue
arrhythmia - MAOI; may cause
 - MAOI; may cause serious reactions (eg,
serious reactions (eg, hyperpyretic crisis,
hyperpyretic crisis, severe convulsions,
severe convulsions, death)
death) - Myocardial infarction
- Myocardial infarction (MI), during the acute
(MI), during the acute recovery period
recovery period
Drug Acecainide
Interactions Aceclofenac
Acemetacin Albuterol
Alfuzosin Amiodarone
Aripiprazole Aspirin
Azithromycin
Bupropion Celecoxib
Chloroquine
Chlorpromazine
Adverse Common Common
Effects Endocrine Gastrointestinal:
metabolic: Weight gain Constipation
Gastrointestinal:
Constipation,
Xerostomia
Neurologic:
Dizziness, Headache,
Somnolence
Ophthalmic: Blurred
vision
Serious Serious
Cardiovascular: Cardiovascular:
Cardiac dysrhythmia, Cardiac dysrhythmia,
Electrocardiogram Heart block,
abnormal, Myocardial Myocardial infarction,
infarction, Prolonged QT Prolonged QT interval,
interval, Sudden cardiac Sudden cardiac death
death Endocrine
 Hematologic: metabolic: Syndrome
Agranulocytosis of inappropriate
Hepatic: antidiuretic hormone
Hepatotoxicity, Jaundice secretion
(rare ) Gastrointestinal:
Neurologic: Paralytic ileus
Neuroleptic malignant Hematologic:
syndrome, Seizure Bone marrow
Psychiatric: depression
Depression, worsening, Hepatic: Fulminant
Suicidal thoughts, hepatic failure,
Suicide Jaundice (rare )
Neurologic:
Cerebrovascular
accident, Myoclonus,
Seizure
Psychiatric:
Depression, worsening,
Mania, Psychotic
disorder, exacerbation,
Suicidal thoughts,
Suicide
Other:
Angioedema
Pregnancy Category C (All
Category Trimesters)
Breastfeedin Compatible with
g breastfeeding (WHO)
Concentration in
Breastmilk at
Therapeutic Dose 0.15
mg/L

Therapeutic Better therapeutic

Drug results were noted with
Concentratio AMITRIPTYLINE plasma
n levels of 50 to 125
ng/mL and
NORTRIPTYLINE plasma
levels not exceeding 95
ng/mL
Time to Peak
Concentration
1) Oral: 4 hours

tab., 10 mg cap 10 mg 1000caps

93.41 500 547.00
cap 25 mg 1000caps
., 25 mg 1,122.00
187.25 500
Depression Depression

Outpatients, 75 mg 25 mg ORALLY 3
orally (divided into to 4 times daily;
1 to 3 doses per alternatively,
day); may increase administer as a
to MAX, 150 mg/day single daily dose;
[2] MAX 150 mg/day

Inpatients, 100 mg Smoking cessation

orally (divided into assistance
1 to 3 doses per
1 week prior to
day); may increase
to MAX, of 300 smoking cessation
mg/day [2] date, 75 to 100
mg/day ORALLY or
Maintenance, 50 to titrate dose to
100 mg orally at desired serum
bedtime levels
recommended for
General Dosage depression;
Information duration of
treatment was 6
Safety and
 effectiveness in to 14 weeks
children below the (study dose)
age of 12 years
have not been Depression
established [2]. adolescents may
Depression receive 30 to 50
mg/day ORALLY (in
(12 years or older) divided doses or
10 mg orally 3 single daily dose)
times a day and 20
mg at bedtime
(manufacturer
dosage) [2]

Antidepressa Suggested
nt Therapeutic Plasma
Concentration
(ng/mL)
Initial
Dose
(mg/day)
Usual
Dosage
Range
(mg/day)
120250b 50150
25 25
100300 50200

Reuptake Antichol Seda Orthos Seiz Conduc

Antagonism inergic tion tatic ures tion
Norepin Sero Effects Hypote Abnorm
ephrine toni nsion alities
n
Amitrip ++ +++ ++++ ++ +++ ++ +++
tyline + ++ +
Nortrip +++ ++ ++ ++ + ++ ++
tyline

Elimi Time Pla Perc Chil

Re Hepa Ger
nati of sm enta dre
nal tic iatr
on Peak a ge n
Fai Insu ic
Half- Plasm Pr Bioa
lur fficie Pat
Life a ote vaila
e/ ncy ien
(hou Conce in ble
Dia ts
rs) ntrati Bin
lys
on din
is
(hours g
) (%
)
Am No cautio 946 15 90 3060 cau Usu
i nee n 97 tion al
d dos
age
(12
yea
rs
or
old
er):
10
mg
oral
ly 3
tim
es
a
day
and
 20
mg
at
bed
tim
e
nor 16 312 87 4670
88 95

Both amitriptyline and nortriptyline are tricyclic antidepressants.

Nortriptyline, a major metabolite of amitriptyline, is a secondary
amine. It is less sedating and better tolerated than amitriptyline.
But both have similar side effects, toxicities, and pharmacologic
activity.

Amitriptyline and nortriptyline are FDA-approved for the treatment

of depression. Amitriptyline has been better studied and its
various off-label uses are better established.

Amitriptyline inhibits serotonin and noradrenaline uptake equally,

whereas nortriptyline is a more potent inhibitor of noradrenaline
than of serotonin uptake38. Nortriptyline has a longer half-life.

Nortriptyline is unique among the antidepressants in that its blood

level exhibits the classical therapeutic window effect37. Blood
concentrations above or below the therapeutic window (60-200
ng/ml) correlate with poor clinical response. Thus, therapeutic
monitoring to ensure the drug level within the therapeutic window
is critical for successful treatment with nortriptyline.

Postherpetic neuralgia
Both amitriptyline and nortriptyline have a similar analgesic action
in postherpetic neuralgia34. Nortriptyline causes fewer side
effects and may be better tolerated than amitriptyline.

Depression
Which antidepressant is more effective? Amitriptyline may be
more effective in the treatment of endogenous depressive illness.

Nortriptyline was compared with amitriptyline in the treatment of

50 patients suffering from primary depression and classified as
reactive and endogenous depressions35. All patients received
promazine hydrochloride in addition to specific antidepressant.
Comparison without diagnostic classification showed no significant
difference in outcome between the two drugs, although
amitriptyline was consistently more effective. The outcome of
endogenous depressions treated with amitriptyline was
significantly better than all other diagnostic groups. Reactive
depressions on amitriptyline showed the least improvement but
not significantly inferior to reactive and endogenous cases on
nortriptyline, the latter two groups having almost identical
outcomes.

Which antidepressant work faster? Nortriptyline provides

more rapid antidepressant effect36.

In a double-blind trial37 after 1 week patients treated with

nortriptyline had a significantly greater mean reduction in
Hamilton depression score (55% compared to 25% for
amitriptyline patients).

34. Watson CP, Vernich L, Chipman M, Reed K. Nortriptyline

versus amitriptyline in postherpetic neuralgia: a randomized trial.
Neurology. 1998 Oct;51(4):1166-71. PubMed
35. Rose JT, Leahy MR, Martin IC, Westhead TT. A comparison
of nortriptyline and amitriptyline in depression. Br J Psychiatry.
1965 Nov
36. Mendels J. Comparative Trial of Nortriptyline and
Amitriptyline in 100 Depressed Patients. Am J Psychiatry. 1968 Feb
37. Lehmann LS, Bowden CL, Redmond FC, Stanton BC.
Amitriptyline and nortriptyline response profiles in unipolar
depressed patients. Psychopharmacology (Berl). 1982
 38. Hyttel J, Christensen AV, Fjalland B. Neuropharmacological
properties of amitriptyline, nortriptyline and their metabolites.
Acta Pharmacol Toxicol (Copenh). 1980z

depression

[50-150 mg PO qhs]
Start: 25-75 mg PO qhs, may incr. by 25-50 mg/day q2-3
days; Max: 300 mg/day; Info: start 10-25 mg PO qhs in elderly
pts, may incr. by 10-25 mg/day q2-3 days; may give in divided
doses; taper dose gradually to D/C

*neuropathic pain, diabetic

[25-100 mg PO qhs]
Start: 25 mg PO qhs, titrate slowly; Max: 150 mg/day; Info:
taper dose gradually to D/C

*post-herpetic neuralgia

[75-150 mg PO qhs]
Start: 10-25 mg PO qhs, may incr. by 10-25 mg/day qwk; Max:
150 mg/day; Info: taper dose gradually to D/C

*migraine headache prophylaxis

[10-100 mg PO qhs]
Start: 10-25 mg PO qhs, titrate slowly; Max: 150 mg/day; Info:
taper dose gradually to D/C

*fibromyalgia

[25-50 mg PO qhs]
Start: 10 mg PO qhs, may incr. by 10-25 mg/day qwk; Max: 75
mg/day; Info: taper dose gradually to D/C

renal dosing

[no adjustment]

hepatic dosing
[not defined]
hepatic impairment: caution advised

Peds Dosing .

Dosage forms: 10,25,50,75,100,125,150

*depression

[9-12 yo]
Dose: 1-3 mg/kg/day PO divided tid; Start: 1 mg/kg/day PO
divided tid x3 days, may incr. by 0.5 mg/kg/day q2-3 days;
Max: 5 mg/kg/day up to 200 mg/day; Info: taper dose
gradually to D/C
[13 yo and older]
Dose: 50-100 mg/day PO divided qd-tid; Start: 10 mg PO tid
and 20 mg qhs, may incr. by 10-25 mg/day q2-3 days; Max:
200 mg/day; Info: taper dose gradually to D/C

*neuropathic pain

[0.5-2 mg/kg PO qhs]

Start: 0.1 mg/kg PO qhs, titrate slowly over 2-3wk; Info: taper
dose gradually to D/C

renal dosing

[no adjustment]

hepatic dosing

[not defined]
hepatic impairment: caution advised
Contraindications / Cautions .

hypersens. to drug/class/compon.

MI, acute recovery

avoid abrupt withdrawal

caution in elderly pts

caution in pts <25 yo

 caution if cardiovascular dz

caution if urinary retention

caution if prostatic hypertrophy

caution if glaucoma, angle-closure

caution if IOP incr.

caution if seizure disorder

caution if thyroid dz

caution if diabetes mellitus

caution if asthma

caution if Parkinson dz

caution if hepatic impairment

caution if schizophrenia

caution if bipolar disorder

caution if electroconvulsive tx

caution if alcohol abuse

caution if suicide risk

caution if GI/GU obstruction

caution if high environmental temperature

Interaction Characteristics:

CYP2C19 substrate

CYP2D6 substrate

anticholinergic effects
 CNS depression

hyperprolactinemic effects, weak

hypertensive effects

hyponatremia

hypotensive effects

lowers seizure threshold

prolongs QT interval (conditional)

serotonergic effects, strong

Serious Reactions

hypotension, orthostatic

HTN

syncope

ventricular arrhythmias

QT prolongation

torsades de pointes

AV block

MI

stroke

seizures

extrapyramidal sx

ataxia

tardive dyskinesia
 paralytic ileus

glaucoma, angle-closure

IOP incr.

agranulocytosis

leukopenia

thrombocytopenia

hallucinations

psychosis exacerbation

hypomania/mania

depression exacerbation

suicidality

SIADH

hepatitis

angioedema

psychosis, anticholinergic

hyperthermia

heat stroke

withdrawal sx if abrupt D/C

Common Reactions

drowsiness

xerostomia

dizziness
 constipation

blurred vision

palpitations

tachycardia

impaired coordination

appetite incr.

nausea/vomiting

diaphoresis

weakness

disorientation

confusion

restlessness

insomnia

anxiety/agitation

urinary retention

urinary frequency

rash/urticaria

pruritus

weight gain

libido changes

impotence

gynecomastia
 galactorrhea

tremor

hypo/hyperglycemia

paresthesia

photosensitivity

Safety/Monitoring .
Therapeutic Drug Levels
120-250 ng/mL (amitriptyline + nortriptyline); Toxic Levels: >500
ng/mL; Timing: just before next dose; Time to Steady State: 2-10
days; Info: max efficacy may take 6wk, not well-correlated w/
levels

Monitoring Parameters
serum drug levels; ECG if cardiovascular dz; BP, HR in peds pts if
dose >3 mg/kg/24h; sx suicidality, clinical worsening, and/or
unusual behavior changes, especially during initial tx or after dose
changes

Look/Sound-Alike Drug Names

[from www.usp.org]

amitriptyline confused with: aminophylline; amlodipine;

imipramine; nortriptyline

Pregnancy/Lactation
Pregnancy
Clinical Considerations

caution advised in 3rd trimester; risk of teratogenicity not

expected based on human data, though risk of neonatal
withdrawal sx based on limited human data w/ other TCAs;
possible dose-dependent risk of teratogenicity based on
conflicting animal data at doses higher than MRHD

Lactation
Clinical Considerations

probably safe; limited information in animals and/or humans

demonstrates no risk/minimal risk of adverse effects to
infant/breast milk production; caution advised

Pharmacology .
Metabolism: liver extensively; CYP450: 1A2, 2D6 (primary), 3A4
substrate; Info: active metabolites incl. nortriptyline

Excretion: urine primarily (18% unchanged), feces; Half-life: 10-

26h (amitriptyline), 18-44h (nortriptyline)

Subclass: Tricyclic Antidepressants (TCAs); Migraine/Headache

Mechanism of Action
exact mechanism of action unknown; inhibits norepinephrine and
serotonin reuptake

Depression
a) SUMMARY: Most studies have indicated that there are no
significant differences between nortriptyline and other
antidepressant drugs of the tricyclic category such as
amitriptyline [1051][1052][1053][1054][1055]
b) Oral nortriptyline 50 to 150 mg/day was as effective as
amitriptyline 100 to 200 mg/day in the treatment of 22
hospitalized unipolar depressed patients [1061]. Of the 22
patients entered in the study, 10 were randomized to receive
amitriptyline and 12 received nortriptyline in a double-blind
manner. Both treatment groups were similar in terms of age, sex
distribution and mean baseline Hamilton Rating Scale (HRS) scores
which were approximately 35. Treatment was initiated with 100
mg nortriptyline or 150 mg amitriptyline. Doses of each drug were
adjusted to achieve plasma concentrations of 60 to 180 ng/mL.
The mean doses at the end of the 4-week study were 131 mg of
amitriptyline and 95 mg of nortriptyline. Four patients (2 from
each group) withdrew from the study because of side effects or
worsening of symptoms. Reductions in HRS scores after 1 week of
treatment were significantly greater in the nortriptyline group than
in the amitriptyline group (55% vs 25%, respectively). There were
no significant differences between groups at weeks 2, 3 and 4;
however, a better outcome was noted for patients in the
nortriptyline group. Patient self-rating global assessments also
reported greater improvement with nortriptyline at 1 week but not
at weeks 2, 3, or 4. Side effects were similar with both drugs. Both
drugs were also unsuccessful in treating unipolar patients who
were delusional.

Postherpetic neuralgia
a) The analgesic action of nortriptyline was as effective as
amitriptyline for the treatment of postherpetic neuralgia in a
double-blind, cross-over trial. Patients (n=31) with
postherpetic neuralgia with at least moderate pain of more
than 3 months' duration received 5 weeks of nortriptyline and
amitriptyline therapy with a 2-week washout period between
treatments. Initial doses of both medications were 10
milligrams (mg) for patients 65 years or older and 20 mg if
younger than 65 years. The dose was increased every 3 to 5
days in 10-mg increments until satisfactory pain relief
occurred or distressing side effects occurred. Patients rated
their pain using a visual analog scale. Pain scores declined
from baseline as time increased with both therapies (p less
than 0.0001). Values for the fifth week showed no significant
differences between the two therapies. Based on pain,
disability, sleep, depression, and satisfaction, similar results
occurred in 21 patients regardless of therapy. Substantial
improvement occurred in 16 patients, and 13 had a good
response on both drugs. Five patients receiving amitriptyline
and 4 receiving nortriptyline had a good response to that drug
 but failed to respond to the other drug. Intolerable side effects
(i.e. dry mouth, constipation, and drowsiness) occurred more
often with amitriptyline than with nortriptyline (p=0.05)
[1062].
[1051] Rose JT, Leahy MR, Martin ICA, et al: A comparison of
nortriptyline and amitriptyline in depression. Br J Psychiatry 1965;
111:1101.

[1052] Leahy MR & Martin ICA: Double-blind comparison of

nortriptyline and amitriptyline in depressive illness. Br J Psychiatry
1967; 113:1433.

[1053] Mendels J: Comparative trial of nortriptyline and

amitriptyline in 100 depressed patients. Am J Psychiatry 1968;
124(suppl):59-62.

[1054] Martin ICA & Leahy MR: Prediction in anti-depressant

therapy. Br J Psychiatry 1968; 114:1289.

[1055] Malitz JS & Kanzler M: Are antidepressants better than

placebo?. Am J Psychiatry 1971; 127:1605.

[1061] Lehmann LS, Bowden CL, Redmond FC, et al: Amitriptyline

and nortriptyline response profiles in unipolar depressed patients.
Psychopharmacology 1982; 77:193-197.

[1062] Watson CP, Vernich L, Chipman M, et al: Nortriptyline

versus amitriptyline in postherpetic neuralgia. Neurology 1998;
51:1166-1171