All posts by Nazila Hassanabadi

Trifluoperazine Hydrochloride – TRIFLUOPERAZINE®

Brand name

  • TRIFLUOPERAZINE®

Drug Class

  • Antianxiety
  • Antiemetic
  • Antipsychotic

Preparations

  • Trifluoperazine Hydrochloride Tablets BP 1, 2, 5, 10 and 20 mg

Indications

  1. Control of excessive anxiety, tension and agitation.
  2. Treatment or prevention of nausea and vomiting of various causes.
  3. Management of psychotic disorders (e.g. acute or chronic catatonic, hebephrenic and paranoid schizophrenia; psychosis due to organic brain damage, toxic psychosis, and the manic phase of manic-depressive illness.)

Pharmacology

  • Phenothiazines act on the subcortical areas of the CNS which influence the affective functions.
  • Antagonist for the postsynaptic mesolimbic dopaminergic D2 receptors in the brain and decreases the release of hypothalamic and hypophyseal hormones.

Metabolism

  • Half Life: 24 hours
  • Onset of action:
    • 5 to 1 hour (following oral administration)
    • 10 to 15 minutes (following intramuscular administration)
    • 5 to 15 minutes (following intravascular administration)
  • Peak of action: 2 hours
  • Metabolism: Liver

Dosing

  • Adults:
    • Mild to moderate symptoms:
      • Usual dosage: 1 or 2 mg twice daily
    • Moderate to severe symptoms:
      • Starting dose: 5 mg orally 2 or 3 times daily
      • Usual dose: 15 to 20 mg/day
      • Max dose: 80 mg/day
  • Children: (6 to 12 years of age):
    • Behavior Disorders in Children:
      • Usual dose is: 1 mg once or twice a day (depends on the child’s bodyweight)
    • Psychotic Children: (either hospitalized or under adequate supervision)
      • Starting dose: 1 mg once or twice daily (depends on the child’s bodyweight)
      • Max dose: 15 mg/day

Drug Interactions

  1. Oral anticoagulants
  2. Propranolol
  3. Anticonvulsants (e.g., phenytoin)
  4. Sedatives
  5. Narcotics
  6. Anesthetics
  7. Tranquilizers
  8. Alcohol
  9. Antihypertensive
  10. Levodopa
  11. Atropine
  12. Organophosphate insecticides
  13. Drugs that prolong Qt interval and torsade de pointes:
    1. Class ia antiarrhythmic (e.g., quinidine, procainamide, disopyramide)
    2. Class iii antiarrhythmic (e.g., amiodarone, sotalol, ibutilide)
    3. Antipsychotics (e.g., chlorpromazine, pimozide, droperidol)
    4. Antidepressants (e.g., fluoxetine, venlafaxine, tricyclic/tetracyclic antidepressants)
    5. Opioids (e.g., methadone)
    6. Macrolide antibiotics and analogues (e.g., erythromycin, clarithromycin)
    7. Quinolone antibiotics (e.g., moxifloxacin)
    8. Pentamidine
    9. Antimalarial
    10. Azole antifungals (e.g., fluconazole, itraconazole, ketoconazole, voriconazole)
    11. Domperidone
    12. Tacrolimus
    13. 5-ht3 antagonists (e.g., dolasetron, ondansetron)
    14. Beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol)
    15. Lithium
  1. Drugs causing electrolyte alteration
  2. SSRIs (selective serotonin reuptake inhibitor) antidepressants

Adverse Effects

  • Extrapyramidal Symptoms
  • Motor Restlessness
  • Neuroleptic Malignant Syndrome
  • Pseudo-parkinsonism
  • Tardive Dyskinesia
  • Cardiovascular
    • nonspecific ECG changes, reversible Q and T wave distortions, QT Prolongation, hypotension, cardiac arrhythmias including atrioventricular block, paroxysmal tachycardia, ventricular fibrillation and cardiac arrest, Ventricular arrhythmias, and Torsade’s de pointes.
  • Haematological
    • Blood dyscrasias including pancytopenia, agranulocytosis, thrombocytopenic purpura, leucopoenia, eosinophilia, haemolytic anaemia, aplastic anaemia.
  • Other Adverse Reactions
    • Skin Reactions, Stimulation, Insomnia, Anorexia, Amenorrhea, Lactation, drowsiness, dizziness, fatigue, blurred vision, seizures, altered CSF proteins, cerebral oedema, prolongation of the action of CNS depressants (opiates, alcohol, barbiturates), autonomic reactions (mouth dryness nasal congestion, headache, nausea, constipation, ileus, impotence, urinary retention, priapism, miosis, and mydriasis), muscular weakness, reactivation of psychotic processes (catatonic-like states), increased aggressiveness, and toxic confusional states

Contraindications

  1. Hypersensitivity
  2. Comatose or greatly depressed
  3. Blood dyscrasias and bone marrow depression
  4. Liver damage
  5. Congenital long QT syndrome or with a family history of this syndrome
  6. Cardiac arrhythmias or Torsade de Pointes.
  7. Combination with serotonin reuptake inhibitors, such as citalopram.

Pregnancy and Breastfeeding

  • Pregnancy: category C
  • Lactation: Not recommended in nursing mothers

Precautions

  1. Increased Mortality in Elderly Patients with Dementia:
    1. the causes of death appeared to be cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia)
  2. Body Temperature Regulation:
    1. Hyperpyrexia might happen with antipsychotic drugs >>> Appropriate care is advised when prescribing Trifluoperazine to patients who will be experiencing conditions which increase core body temperature (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity or being subject to dehydration.)
  3. Potential for Hypotension:
    1. High risk group: elderly or debilitated patients
    2. Avoid hypotension by:
      1. Large doses should be avoided in patients with impaired cardiovascular systems.
      2. After initial administration, keep patient lying down and observe for at least 0.5 hour.
    3. If hypotension occurs:
      1. Place patient in head-low position with legs raised.
      2. norepinephrine or phenylephrine can be used as vasoconstrictor
  4. Increase in mental and physical activity:
    1. In angina patients this effect is not desirable >>> patients with angina pectoris experience increasing their pain while taking trifluoperazine >>> patients should be observed carefully
  5. Prolongation of QT Interval:
    1. Caution in patients with cardiovascular disease or family history of QT prolongation.
    2. Avoid concomitant QT prolonging drugs.
    3. Caution when administering in patients with risk factors for Torsade de Pointes:
      1. Female
      2. Age 65 years or older
      3. Baseline prolongation of the qt/qtc interval
      4. Congenital long qt syndromes
      5. Family history of qt prolongation, or sudden cardiac death at <50 years
      6. Cardiac disease
      7. History of arrhythmias
      8. Electrolyte disturbances
      9. Bradycardia
      10. Acute neurological events
      11. Hepatic dysfunction, renal dysfunction, and phenotypic/genotypic poor metabolizers of drug
      12. Diabetes mellitus
      13. Nutritional deficit
      14. Autonomic neuropathy
  1. Caution patient about endocrine and Metabolism side effects of trifluoperazine:
    1. Hyperprolactinaemia: which may cause galactorrhoea, gynecomastia, oligo-menorrhea or amenorrhoea, and erectile dysfunction, hypogonadism which may lead to decreased bone mineral density in both female and male subjects.
    2. Hyperglycemia: Patients should have baseline and periodic monitoring of blood glucose and body weight.
  2. Caution patients about Gastrointestinal side effects:
    1. The antiemetic action of trifluoperazine may mask signs and symptoms of toxicity or over dosage of other drugs
    2. Might obscure the diagnosis of conditions such as intestinal obstruction, brain tumor and Reye’s syndrome.
  3. Caution patient about possibility of priapism.
  4. Caution patient about hematologic problems:
    1. Blood dyscrasias (agranulocytosis, anemia, leukopenia, neutropenia, pancytopenia, and thrombocytopenia) and jaundice of the cholestatic type might happen >>> hematological monitoring is recommended.
  5. Venous thromboembolism (VTE):
    1. All potential risk factors for VTE should be identified and preventative measures undertaken.
  6. Caution patients about Hepatic/Biliary/Pancreatic:
    1. Jaundice of the cholestatic type of hepatitis or liver damage might happen in patients receiving trifluoperazine >>> Hepatic and renal function should be checked
  7. Caution patients about Neurologic side effects:
    1. Neuroleptic Malignant Syndrome (NMS)
    2. Tardive Dyskinesia
  8. Caution in concomitant use with Anticonvulsants:
    1. Trifluoperazine lower the convulsive threshold >>> it should be used with caution in patients with epilepsy, EEG abnormalities or subcortical brain damage.
  9. Caution patients about effects on Driving Ability and Use of Machinery:
    1. Trifluoperazine impair mental and/or physical abilities >>> patients should be cautioned about activities requiring alertness (e.g., operating vehicles or machinery).
  10. Caution patients about Dependence/Tolerance:
    1. Sudden discontinuance in long-term psychiatric patients cause temporary symptoms (e.g., nausea and vomiting, dizziness, tremulousness.)
  11. Caution patients about Ophthalmologic problem:
    1. Glaucoma: trifluoperazine should be used with caution in patients with glaucoma.
    2. Retinopathy: Phenothiazines might produce retinopathy, especially with long-term treatment at high dosage.
  12. Caution patients about reversible skin pigmentation
  13. Special Populations:
    1. Pediatrics (under 6 years of age):
      1. Not recommended in children under the age of 6.
    2. Geriatrics (≥65 years of age):
      1. Not recommended in patients 65 years of age or older
      2. Caution should be exercised with the use of Trifluoperazine in the elderly patient.
    3. Use in Geriatric Patients with Dementia
      1. Care should be exercised in treating elderly or debilitated patients.
  14. Monitoring and Laboratory Tests:
    1. Phenothiazines result in falsely positive or negative pregnancy test results >>> Caution patients about reliability of pregnancy test during usage of trifluoperazine.

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

Chlorpromazine Hydrochloride – LARGACTIL®

Brand name

  • LARGACTIL®

Drug Class

  • 1st generation Antipsychotics, Phenothiazines
  • Tranquillizer

Preparations

  • Tablet: 10 mg, 25 mg, 100 mg
  • Syrup (100ml): 25mg/5ml:
  • Ampoules (2ml): 25mg/ml

Indications

  1. Acute functional psychosis (e.g. schizophrenia, mania or psychotic depression).
  2. Long-term treatment of schizophrenia.
  3. Short-term treatment of:
    1. Agitation and behavioral disturbance in patients with delirium or dementia.
    2. Agitation and severe depression.
  4. Severe behavioral disturbances, as can be found in some children with mental retardation or autism (including self-injurious, aggressive behavior or over activity.)
  5. In management of terminal illness:
    1. To enhance the effect of analgesics.
    2. To control nausea and vomiting.
  6. Control of intractable hiccough.

Pharmacology

  • Antagonize dopamine D2 receptors in brain;
  • Depresses release of hypothalamic and hypophyseal hormones;
  • Depress reticular activating system;
  • Inhibits prolactin-release-inhibitory factor and stimulating the release of prolactin.

Metabolism

  • Absorption:
    • Absorption route: gastrointestinal tract
    • Bioavailability: extensive first pass metabolism in the gut and the liver
    • Onset of action: 30-60 min
    • Duration of action: 4-6 hours, extended release: 10-12 hours
    • Peak plasma level:
      • following oral administration: 1-4 hours
      • Following intramuscular injection: 15 – 30 minutes.
  • Distribution:
    • Widely distributed to the body tissue.
    • It crosses the blood-brain barrier and achieves higher concentrations in the brain than in the plasma.
    • Protein-bound: 90 – 99%
  • Metabolism:
    • Metabolize pathway: by hepatic P450 enzyme CYP2D6
    • extensive first pass metabolism after oral administration
    • Chlorpromazine is almost completely metabolized.
  • Elimination:
    • Half-life: 30 hours
    • Excretion: Significantly in the urine, in small amounts in faeces and in lesser amounts in sweat and hair.

Dosing

  • Adults:
    • Oral:
      • initial dose for ambulant patients: 25 mg three times daily
      • Max dose: 600mg-800mg per day.
      • maintenance doses: 25 to 100 mg three times daily
      • Crushing the tablets is not recommended, therefore Syrup should be replaced.
    • Parenteral:
      • deep intramuscular injection or intravenous infusion (after dilution with normal saline)
      • Blood pressure and vital signs should be taken before and monitored closely after injections.
      • Usual single dose: 25 to 50 mg by deep intramuscular injection (if necessary; repeat three to four times in 24 hours.)
      • Intramuscular injection part: upper outer quadrant of the buttock or upper portion of the deltoid muscle.
  • Children:
    • Over 5 years of age: one third to one half of adult dosage is given
    • Younger than 5 years old: oral dose is calculated on the basis of 0.5 mg/kg bodyweight.
      • 5 mg at 1 year
      • 5 mg at 3 years
      • 10 mg at 6 years.
    • Doses may be repeated three or four times a day.
    • Children need to be monitored for hypothermia and hypotension.
  • Hepatic or Renal Impairment:
    • The dosage in these patients may need to be reduced
  • Elderly or Debilitated:
    • The dosage in these patients may need to be reduced

Drug Interactions

  1. Interactions resulting in decreased chlorpromazine levels:
    • Food,
    • Alcohol
    • Benztropine
    • Antacids
    • Lithium
    • Chronic administration of barbiturates
  2. Interactions resulting in increased chlorpromazine levels:
    • Tricyclic antidepressants
    • CYP1A2 inhibitors: ciprofloxacin, fluvoxamine, oral contraceptives, thiabendazole, vemurafenib
  3. Interactions in which other drugs are affected by chlorpromazine:
    • Central nervous system depressants, benzodiazepines, anesthetic drugs, opioids, barbiturates, lithium, valproic acid, phenytoin, propranolol, adrenaline, guanethidine, clonidine, antidiabetic agents, levodopa, amphetamines, oral anticoagulants, Thiazide diuretics, quinidine, MAOIs, suxamethonium, organophosphorus insecticides, atropine, desferrioxamine.
  4. Interaction with drugs that:
    • increase risk of QT prolongation:
      • Class Ia antiarrhythmic agents: quinidine and disopyramide.
      • Class III antiarrhythmic agents: amiodarone and sotalol.
      • Other medications: bepridil, cisapride, sultopride, thioridazine, methadone, intravenous erythromycin, intravenous vincamine, halofantrine, pentamidine, sparfloxacin.
    • Induce bradycardia:
      • Calcium channel blockers (diltiazem, verapamil), beta-blockers, clonidine, guanfacine, and digitalis.
    • Cause hypokalemia:
      • Diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactides.

Adverse Effects

More Common Adverse Effects

  • Cardiovascular: Postural hypotension, ECG Changes.
  • Dermatological: Contact dermatitis, photosensitivity, urticarial, maculopapular, petechial or edematous reactions.
  • Endocrine: Elevated prolactin levels, impaired thermoregulation, hyperglycemia, other hypothalamic effects.
  • Gastrointestinal: Dry mouth, constipation.
  • Immunological: Raised ANA titer, positive SLE cells.
  • Genitourinary: Urinary retention.
  • Hematological: Leucopenia, agranulocytosis, eosinophilia, hemolytic anemia, aplastic anemia, thrombocytopenic purpura and pancytopenia have been reported.
  • Nervous System:
    • Autonomic: dry mouth, mental confusion, postural hypotension, nasal congestion, nausea, obstipation, constipation, adynamic ileus, urinary retention, priapism, miosis and mydriasis, atonic colon, ejaculatory disorders/impotence.
    • Central: extrapyramidal reactions (Parkinsonism, akathisia) tardive dyskinesia, non-extrapyramidal effects including lowering of seizure threshold and paradoxical effects, e.g. agitation, excitement and aggravation of schizophrenic symptoms; drowsiness, dystonia, motor restlessness.
  • Ocular: Blurred vision, photophobia, miosis, mydriasis, corneal deposits.
  • Respiratory: Stuffy nose, respiratory depression.
  • Local Reactions (injection): Pain at injection site, injection abscess.
  • General: Weight gain.

 Less Common Adverse Effects

  • Cardiovascular: Arrhythmias, hypertensive crisis (following abrupt withdrawal), A-V block, ventricular tachycardia, QT interval prolongation and fibrillation, sudden death
  • Dermatological: Skin pigmentation and purpura, exfoliative dermatitis and toxic epidermal necrolysis.
  • Endocrine: Hyperthermia, hypothermia, lactation and moderate breast engorgement in females on large doses, false-positive pregnancy tests, amenorrhea, gynecomastia, hypoglycemia, glycosuria.
  • Gastrointestinal: Paralytic ileus.
  • General: systemic lupus erythematosus, Allergic reactions
  • Genitourinary: Inappropriate ADH secretion, water retention, edema, incontinence.
  • Hematological: Coagulation defects.
  • Hepatic: Cholestatic jaundice and liver injury.
  • Musculoskeletal: Neuroleptic malignant syndrome, myasthenia gravis.
  • Nervous System: Fits, cerebral edema, nightmares, abnormality of cerebrospinal fluid proteins.
  • Ocular: Precipitation/aggravation of narrow angle glaucoma, optic atrophy, pigmentary retinopathy, lens opacities.
  • Psychiatric: Dysphoria, catatonic excitement.

 Serious or Life Threatening Reactions

  • Hypothermia or hyperthermia
  • Cardiac arrhythmia
  • Agranulocytosis
  • Progressive hepatic fibrosis
  • Malignant hyperpyrexia
  • Sudden Death
  • Tardive Dyskinesia
  • Neuroleptic Malignant Syndrome

 Other adverse effects

  • Metabolism and nutrition disorders: Hyper-triglyceridaemia, hyponatremia, Glucose intolerance and hyperglycemia
  • Gastrointestinal disorders: Colitis ischemic, gastrointestinal necrosis, necrotizing colitis, intestinal perforation.
  • Skin and subcutaneous tissue disorders: Angioedema, urticaria.

Contraindications

  1. Circulatory collapse
  2. CNS depression (e.g. coma or drug intoxication.)
  3. Previous history of a hypersensitivity reaction
  4. Bone marrow depression
  5. Pheochromocytoma
  6. Hepatic failure or active hepatic disease.
  7. LARGACTIL Syrup contains sodium metabisulfite, sodium sulfite and sodium benzoate and LARGACTIL Injection contains sodium metabisulfite and sodium sulfite and may cause allergic-type reactions including anaphylactic symptoms and asthmatic episodes in susceptible people.

Pregnancy and Breastfeeding

  • Pregnancy: Category C
  • Lactation: not recommended for nursing mothers

Precautions

  1. Should not be used in: Epilepsy, Parkinson’s disease, hypoparathyroidism, myasthenia gravis and prostatic hypertrophy.
  2. Antiemetic Effects: The antiemetic effects of chlorpromazine may mask signs of over-dose of toxic drugs or diagnosis of intestinal obstruction and brain tumor.
  3. Temperature Regulation: Phenothiazine depress the mechanism for regulation of temperature >>> Severe hypothermia may occur during swimming in cold water or in patients receiving antipyretic therapy, and heat stroke may occur in hot weather.
  4. Prolonged Usage: Long term usage could cause the development of tardive dyskinesia.
  5. Alertness: Chlorpromazine impair mental and physical abilities (especially during the first few days of therapy.) >>> caution patients about activities requiring alertness.
  6. Agranulocytosis:
    1. Agranulocytosis has been reported at an incidence of between 1:1,300 and 1:500,000. Most reported cases have occurred between the fourth and tenth week of treatment.
    2. Warn patients to report the sudden appearance of sore throat, fever or other signs of infection. If white blood cell and differential counts indicate cellular depression, stop treatment and start antibiotic and other suitable therapy, subject to the expert guidance of a hematologist.
  7. Liver Dysfunction:
    1. Because of extensive hepatic metabolism chlorpromazine >>> caution should be taken in treating patients with hepatic impairment >>> Dose reduction is necessary.
    2. If bilirubinemia, bilirubinuria or icterus occur >>> discontinued treatment
  8. Retinopathy: Periodic eye examinations should be performed during prolonged therapy.
  9. Respiratory Disease: Chlorpromazine might suppress cough reflex >>> aspiration of vomitus is possible >>> Chlorpromazine should be used with caution in patients with chronic respiratory disorders.
  10. Reye’s syndrome:
    1. Chlorpromazine should be avoided in children and adolescents with signs and symptoms of Reye’s syndrome.
    2. The extrapyramidal symptoms which can occur secondary to chlorpromazine may be confused with the central nervous system signs of Reye’s syndrome or other encephalopathy.
  11. Renal disease: Chlorpromazine should be given cautiously to patients with renal disease.
  12. Glaucoma and Neuroleptic Malignant Syndrome: Should be used with caution in patients with glaucoma and features of neuroleptic malignant syndrome include autonomic dysfunction.
  13. Photosensitivity: Patients should be warned about photosensitivity in sunny weather.
  14. Hypotension: Extreme caution in cardiovascular disease, hemochromocytoma, conditions with a sudden drop in blood pressure, usage in conjunction with other drugs which cause postural hypotension.
  15. QT Intervals: Phenothiazines potentiate QT interval prolongation >>> increases the risk of the torsade de pointes.
  16. Cerebrovascular Events: There is an increased risk of cerebrovascular events in elderly patients with dementia.
  17. Venous Thromboembolism: chlorpromazine should be used with caution in patients with risk factors for thromboembolism
  18. Use in the Elderly: Elderly are more susceptible to the adverse effects >>> starting dose should be about half the usual adult dose and dosage increments should be gradual and reviewed regularly.
  19. Elderly Patients with Dementia: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
  20. Hyperglycemia: Hyperglycemia or glucose intolerance might happen >>> Diabetic patients or patients with risk factors of diabetes should get glycemic monitoring during treatment.
  21. Effects on Fertility: Chlorpromazine may cause hyperprolactinemia >>> associated with impaired fertility in women.
  22. Effect on Laboratory Tests: Phenothiazines might produce false positive phenylketonuria (PKU) test results.
  23. Over-dose:
    1. Symptoms: CNS depression, drowsiness, coma, areflexia, restlessness, confusion, excitement, hypotension, tachycardia, hypothermia, pupillary constriction, tremor, muscle twitching, spasm or rigidity, convulsions, muscular hypotonia, difficulty in swallowing and breathing, cyanosis and respiratory and/or vasomotor collapse, sudden apnea, Polyuria has also been noted which may result in dehydration
    2. Treatment: Symptomatic and supportive treatment should be administered.

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

Pimozide – Pr PIMOZIDE®

Brand name

  • Pr PIMOZIDE

Drug Class

  • Antipsychotic, 1st generation

Preparations

  • Pimozide Tablets USP 2 mg and 4 mg

Indications

  • Management of the manifestations of chronic schizophrenia in which the main manifestations do not include excitement, agitation or hyperactivity.

Pharmacology

  • Mechanism of Action:
    • The basic mechanism of action is related to its action on central aminergic receptors.
    • It has a selective ability to block central dopaminergic receptors, although it affects noradrenaline turnover at higher doses.

Metabolism

  • Pharmacokinetics
    • Absorption: More than 50%
    • Peak serum level: 6-8 hours
    • Metabolism:
      • Undergo significant first-pass metabolism.
      • Pimozide is extensively metabolized in the liver.
    • Mean elimination half-life: 55 hours.
    • Excretion: kidney

Dosing

  • Adults:
    • Usual Starting Dose: 2 to 4 mg once daily, with weekly increments of 2 to 4 mg until a satisfactory level of therapeutic effect is attained or excessive adverse effects occur.
    • Maintenance Therapy: 6 mg daily
    • Max dose: 20 mg
  • Missed Dose:
    • Patient should take the dose as soon as possible and continue with their regular schedule.
    • If it is almost time for the next dose: patient should skip the missed dose and continue with the next scheduled dose.

Drug Interactions

  1. Drugs acting on CNS:
    1. Anesthetics, opiates, alcohol, atropine, organophosphorous, amphetamines.
  2. Levodopa
  3. Anti-hypertensives
  4. Drugs That Inhibit Cytochrome P450:
    1. aprepitant, azole antimycotics, antiviral protease inhibitors, macrolide antibiotics, nefazodone.
  5. Drugs That Prolong QT Interval:
    1. Class IA antiarrhythmics (quinidine, procainamide, disopyramide)
    2. Class III antiarrhythmics (amiodarone, sotalol, ibutilide)
    3. Class 1C antiarrhythmics (flecainide, propafenone)
    4. antipsychotics (chlorpromazine, pimozide, haloperidol, droperidol)
    5. antidepressants (fluoxetine, venlafaxine, tricyclic/tetracyclic antidepressants)
    6. opioids (methadone)
    7. macrolide antibiotics and analogues (erythromycin, clarithromycin, telithromycin)
    8. quinolone antibiotics (moxifloxacin, gatifloxacin)
    9. pentamidine
    10. antimalarials (quinine)
    11. azole antifungals (fluconazole, itraconazole, ketoconazole, voriconazole)
    12. domperidone
    13. 5-HT3 antagonists (dolasetron, ondansetron)
    14. tacrolimus
    15. beta-2 adrenoceptor agonists (salmeterol, formoterol)
    16. Lithium
  6. Drugs causing electrolyte alteration:
    1. Diuretics (particular those causing hypokalemia.)
    2. Laxatives and enemas
    3. Amphotericin B
    4. High dose corticosteroids
  7. SSRI (Selective Serotonin Reuptake Inhibitor) Antidepressants:
    1. sertraline
    2. citalopram
    3. paroxetine
  8. Drug-Food Interactions
    1. Grapefruit Juice
  9. Drug-Herb Interactions
    1. Betel Nut

Adverse Effects

  • Blood and Lymphatic System Disorders:
    • Blood dyscrasias (agranulocytosis, anemia, aplastic anemia, eosinophilia, granulocytopenia, leukopenia, neutropenia, pancytopenia, and thrombocytopenic purpura), bone marrow failure, disseminated intravascular coagulation, leukocytosis, lymphadenopathy, polycythaemia, and thrombocytopenia.
  • Cardiac Disorders:
    • angina pectoris, arrhythmia, coronary atherosclerosis, atrioventricular block, cardiac arrest, cardiac failure, cardiac valve disease, cardio-respiratory arrest, cardiomegaly, coronary artery disease, myocardial infarction, myocardial ischemia, myocarditis, stress cardiomyopathy, torsade de pointes, ventricular tachycardia, ventricular fibrillation.
  • Congenital, Familial and Genetic Disorders:
    • Congenital anomaly, congenital hydronephrosis, double ureter, dysmorphism, macrocephaly, microphthalmos, skull malformation, Tourette’s disorder, urinary tract malformation, ventricular septal defect.
  • Endocrine Disorder:
    • Increased blood prolactin, hyperglycemia (in patients with pre-existing diabetes), hyperprolactinemia, hyperthyroidism, inappropriate antidiuretic hormone secretion.
  • Eye Disorder:
    • Accommodation disorder, glaucoma, oculogyration, blurred vision, visual impairment.
  • Gastrointestinal Disorders:
    • Constipation, diarrhea, dry mouth, hemorrhagic enterocolitis, fecal incontinence, intestinal ischemia, pancreatitis, salivary hypersecretion, sub ileus, vomiting.
  • General Disorder and Administration Site Conditions:
    • Asthenia, death, drug interaction, face edema, fatigue, hyperthermia, hypothermia, macrosomia, malaise, pyrexia.
  • Hepatobiliary Disorders:
    • Abnormal hepatic function, hepatitis, hepatomegaly, liver injury.
  • Immune System Disorders:
    • Antiphospholipid syndrome.
  • Infections and Infestations:
    • Bacterial infection, bacterial toxemia, bronchitis, bronchopneumonia, pneumonia, pustular rash.
  • Injury, Poisoning and Procedural Complications:
    • Accidental exposure, contusion, drug dispensing error, drug toxicity, fall, femoral neck fracture, overdose, wound.
  • Investigations:
    • increased blood creatinine phosphokinase, increased blood phosphorus, decreased blood pressure, increased blood pressure, breath sounds, circulating coagulant, increased drug level, abnormal electrocardiogram (repolarization, ST segment depression, T wave inversion, T wave peaked), prolonged electrocardiogram QT interval, abnormal electroencephalogram, decreased hematocrit, decreased hemoglobin, increased hepatic enzyme, decreased red blood cell count, increased red cell distribution width, increased respiratory rate, increased transaminases, increased weight, decreased white blood cell count, increased white blood cell count.
  • Metabolism and Nutrition Disorders:
    • Decreased appetite, diabetes mellitus (type I and type II), dyslipidemia, reduced fluid intake, hyper-phagia, hypoglycemia, hypokalemia, hyponatremia, ketoacidosis.
  • Musculoskeletal and Connective Tissue Disorders:
    • Arthralgia, muscle rigidity, myalgia, nuchal rigidity, rhabdomyolysis, soft tissue hemorrhage, systemic lupus erythematosus.
  • Benign, Malignant and Unspecified Neoplasms (Including Cysts and Polyps):
    • Endometrial cancer, myelodysplastic syndrome.
  • Nervous System Disorders:
    • akathisia, altered state of consciousness, bradykinesia, cognitive disorder, cogwheel rigidity, coma, convulsion, dementia, disturbance in attention, dizziness, drooling, dyskinesia, dystonia, epilepsy, extrapyramidal disorder, grand mal convulsion, hemorrhagic cerebral infarction, headache, hypoesthesia, hypo-kinesia, hypoxic-ischemic encephalopathy, loss of consciousness (syncope), lethargy, masked facies, mental retardation, neuroleptic malignant syndrome, parkinsonism, somnolence, stupor, tardive dyskinesia, tremor, unresponsive to stimuli.
  • Pregnancy, Puerperium and Prenatal Conditions:
    • Missed abortion, spontaneous abortion.
  • Psychiatric Disorder:
    • abnormal behavior, aggression, agitation, apathy, confusional state, decreased activity, delusion, depression, disorientation, drug dependence, euphoric mood, hallucination, insomnia, decreased libido, mutism, psychomotor retardation, restlessness, schizophrenia, self-injurious behavior, sleep disorder, suicide, suicide attempt, withdrawal syndrome.
  • Renal and Urinary Disorders:
    • Anuria, glycosuria, hematuria, nephrotic syndrome, renal failure, urinary incontinence, urinary retention.
  • Reproductive System and Breast Disorder:
    • Amenorrhea, breast cysts, erectile dysfunction, galactorrhea, gynecomastia.
  • Respiratory, Thoracic and Mediastinal Disorders:
    • Asphyxia, bradypnea, dyspnea, hypoxia, lung disorder, oropharyngeal spasm, pulmonary congestion, pulmonary embolism, pulmonary edema, pulmonary thrombosis, respiratory arrest.
  • Skin and Subcutaneous Tissue Disorders:
    • Angioedema, hyperhidrosis, photosensitivity reaction, pruritus, rash (exfoliative, erythematous, and popular), skin exfoliation, skin toxicity, toxic skin eruption, urticarial.
  • Vascular Disorders:
    • Arteriosclerosis, circulatory collapse, deep vein thrombosis, venous embolism, hematoma, hypertension (orthostatic), phlebitis, shock, thrombosis.

Contraindications

  1. Hypersensitive to drug
  2. Central nervous system depression
  3. Brain damage
  4. Comatose states
  5. Liver disorders
  6. Renal insufficiency
  7. Pheochromocytoma
  8. Blood dyscrasias
  9. Depressive disorders
  10. Parkinson’s syndrome
  11. congenital long QT syndrome or a family history of this syndrome
  12. cardiac arrhythmias or Torsade de Pointes
  13. Combination with CYP 3A4 and CYP 2D6 inhibiting drugs:
    1. Azole anti-mycotics, antiviral protease inhibitors, macrolide antibiotics and nefazodone, quinidine.
  14. The treatment of simple tics or tics other than those associated with Tourette’s Disorder.
  15. Combination with serotonin reuptake inhibitors:
    1. sertraline, paroxetine, citalopram and escitalopram
  16. A scheduled regional or spinal anesthesia.

Pregnancy and Breastfeeding

  • Pregnancy: Category C
  • Lactation: Not recommended in nursing mothers

Precautions

  1. Body Temperature Regulation:
    1. Disruption of the body’s ability to reduce core body temperature >>> Hyperpyrexia might happen
  2. Caution about Cardiovascular side effects:
    1. QT prolongation
    2. ventricular arrhythmias (Ventricular tachycardia, ventricular fibrillation)
    3. Sudden death and cardiac arrest (very rare)
    4. Potential for Hypotension
    5. Torsade de Pointes, Risk factors:
      1. female
      2. age 65 years or older
      3. baseline prolongation of the QT/QTc interval
      4. presence of genetic variants affecting cardiac ion channels or
      5. regulatory proteins, especially congenital long QT syndromes
      6. family history of QT prolongation, or sudden cardiac death at <50 years
      7. cardiac disease (e.g., myocardial ischemia or infarction, congestive heart failure, left ventricular hypertrophy, cardiomyopathy, conduction system disease)
      8. history of arrhythmias (especially ventricular arrhythmias, atrial fibrillation, or recent conversion from atrial fibrillation)
      9. electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia)
      10. bradycardia (<50 beats per minute)
      11. acute neurological events (e.g., intracranial or subarachnoid hemorrhage, stroke, intracranial trauma)
      12. nutritional deficits (e.g., eating disorders, extreme diets)
      13. diabetes mellitus,
      14. autonomic neuropathy
      15. hepatic dysfunction, renal dysfunction, and/or phenotypic/genotypic poor metabolizers of drug metabolizing enzyme isoforms
    6. ECG should be performed prior to initiation of treatment with pimozide, as well as periodically during treatment.
  1. Endocrine and Metabolism
    1. Hyperprolactinemia (cause galactorrhea, gynecomastia, oligo-menorrhea or amenorrhea, and erectile dysfunction.)
    2. Caution in patients with a previously detected breast cancer.
    3. Long-standing hyperprolactinemia causes hypogonadism >>> leads to decreased bone mineral density.
    4. Hyperglycemia:
      1. Diabetic ketoacidosis (DKA) might occur
      2. Patients should have baseline and periodic monitoring of blood glucose and body weight.
  2. Gastrointestinal:
    1. Pimozide has a substantial antiemetic effect >>> caution in cases where the suppression of nausea and vomiting might hinder the diagnosis of an underlying physical disorder.
  3. Genitourinary;
    1. Caution patient about priapism.
  4. Hematologic:
    1. Neutropenia, leukopenia, granulocytopenia, agranulocytosis and anemia might occur >>> complete blood count (CBC) tested should be done prior to starting pimozide.
  5. Patient should be cautioned about Venous thromboembolism (VTE)
  6. Hepatic/Biliary/Pancreatic:
    1. Caution is advised in patients with liver disease because pimozide is metabolized in the liver.
  7. Neurologic
    1. Increased Psychomotor Activity:
      1. Should not be used in the management of chronic schizophrenia with main symptoms of agitation, excitement and anxiety.
    2. Neuroleptic Malignant Syndrome:
      1. Hyperthermia (early sign), generalized muscle rigidity, autonomic instability, and altered consciousness.
    3. Tardive Dyskinesia
    4. Withdrawal Emergent Neurological Signs:
      1. Gradual withdrawal of antipsychotic drugs is recommended
    5. Schizophrenia:
      1. Response to antipsychotic drug treatment may be delayed >>> Gradual withdrawal is advisable.
    6. Extrapyramidal Symptoms
    7. Seizures:
      1. pimozide might lower the convulsive threshold >>> should be used with caution in epileptic patients
    8. Effects on Driving Ability and Use of Machinery:
      1. Patients should be warned of the risks of sedation and advised not to drive or operate machinery during treatment
  8. Pediatrics (<18 years of age):
    1. Not recommended for use in the pediatric age group.
  9. Geriatrics (≥65 years of age):
    1. Caution should be exercised with the use of pimozide in the elderly
    1. Use in Geriatric Patients with Dementia:
      1. Pimozide is not indicated in elderly patients with dementia.
  10. Over dosage:
    1. Symptoms:
      1. Exaggeration of known pharmacologic effects and adverse reactions, extrapyramidal symptoms, cardiac arrhythmias.
    2. Treatment:
      1. No specific antidote for pimozide
      2. Treatment is mainly supportive.

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

Schizophrenia

What is schizophrenia?

Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels, and behaves. People with schizophrenia may seem like they have lost touch with reality. Although schizophrenia is not as common as other mental disorders, the symptoms can be very disabling.

What are the risk factors of schizophrenia?

Risk Factors:

Genes and environment: Scientists have long known that schizophrenia sometimes runs in families. However, there are many people who have schizophrenia who don’t have a family member with the disorder and conversely, many people with one or more family members with the disorder who do not develop it themselves.

Scientists believe that many different genes may increase the risk of schizophrenia, but that no single gene causes the disorder by itself. It is not yet possible to use genetic information to predict who will develop schizophrenia.

Scientists also think that interactions between genes and aspects of the individual’s environment are necessary for schizophrenia to develop. Environmental factors may involve:

  • Exposure to viruses
  • Malnutrition before birth
  • Problems during birth
  • Psychosocial factors

Different brain chemistry and structure: Scientists think that an imbalance in the complex, interrelated chemical reactions of the brain involving the neurotransmitters (substances that brain cells use to communicate with each other) dopamine and glutamate, and possibly others, plays a role in schizophrenia.

Some experts also think problems during brain development before birth may lead to faulty connections. The brain also undergoes major changes during puberty, and these changes could trigger psychotic symptoms in people who are vulnerable due to genetics or brain differences.

The risk of development of schizophrenia in the general population for someone with no family history of mental illness is estimated at approximately 1%. This risk increases to approximately 3% if a person in the extended family, for instance an aunt or uncle, has been diagnosed with schizophrenia.

When one parent has schizophrenia the risk is estimated at 13% for a child. The risk is highest among identical twins when one is diagnosed with schizophrenia the other has 50% chance of developing schizophrenia. It is important to note that even in identical twins there is still 50% chance that the other twin does not develop the condition. This proves that importance of the environmental factors in developing schizophrenia.

What other conditions could present with symptoms of schizophrenia?

Symptoms of schizophrenia can be similar to conditions that could cause hallucination or paranoid thinking. Stimulant drugs such as cocaine and amphetamines are among the most common drugs that could present with symptoms of schizophrenia.

Marijuana use has been linked strongly to presentation of schizophrenia. Individuals who start smoking marijuana at teen age, are at strong risk of developing psychosis and or symptoms of schizophrenia.

Other psychedelic drugs such as PCP, mushrooms and some prescription medications could cause psychosis and present with symptoms of schizophrenia.

What are the symptoms and signs of schizophrenia?

Symptoms of schizophrenia usually start between ages 16 and 30. In rare cases, children have schizophrenia too.

The symptoms of schizophrenia fall into three categories: positive, negative, and cognitive.

Positive symptoms: “Positive” symptoms are psychotic behaviors not generally seen in healthy people. People with positive symptoms may “lose touch” with some aspects of reality. Symptoms include:

  • Hallucinations
  • Delusions
  • Thought disorders (unusual or dysfunctional ways of thinking)
  • Movement disorders (agitated body movements)

Negative symptoms: “Negative” symptoms are associated with disruptions to normal emotions and behaviors. Symptoms include:

  • “Flat affect” (reduced expression of emotions via facial expression or voice tone)
  • Reduced feelings of pleasure in everyday life
  • Difficulty beginning and sustaining activities
  • Reduced speaking

Cognitive symptoms: For some patients, the cognitive symptoms of schizophrenia are subtle, but for others, they are more severe and patients may notice changes in their memory or other aspects of thinking. Symptoms include:

  • Poor “executive functioning” (the ability to understand information and use it to make decisions)
  • Trouble focusing or paying attention
  • Problems with “working memory” (the ability to use information immediately after learning it)

Are there any laboratory work up for diagnosing schizophrenia?

Although there are no specific diagnostic test for diagnosing schizophrenia, clinicians could use a variety of tools to exclude the other health conditions that could present with psychosis and other symptoms of schizophrenia. CT scan and fMRI often are used to exclude structural causes of psychosis such as brain tumor, changes to brain function and damages to brain tissue.

How is schizophrenia managed?

Because the causes of schizophrenia are still unknown, treatments focus on eliminating the symptoms of the disease. Treatments include:

Antipsychotics

Antipsychotic medications are usually taken daily in pill or liquid form. Some antipsychotics are injections that are given once or twice a month. Some people have side effects when they start taking medications, but most side effects go away after a few days. Doctors and patients can work together to find the best medication or medication combination, and the right dose.

Psychosocial Treatments

These treatments are helpful after patients and their doctor find a medication that works. Learning and using coping skills to address the everyday challenges of schizophrenia helps people to pursue their life goals, such as attending school or work. Individuals who participate in regular psychosocial treatment are less likely to have relapses or be hospitalized.

Coordinated specialty care (CSC)

This treatment model integrates medication, psychosocial therapies, case management, family involvement, and supported education and employment services, all aimed at reducing symptoms and improving quality of life.

What can be done to reduce the risk of development of schizophrenia?

  • Avoid street drugs
  • Limit drinking alcohol to safe drinking levels
  • Improve and enhance social skills
  • Avoid social isolation
  • Make an ongoing effort to maintain social connections and network
  • Learn how to handle anxiety and panic
  • Have healthy lifestyle
  • Seek help as soon as you experience symptoms of mental illnesses
  • Follow healthy diet guides
  • Begin prenatal planning at least 3 months in advance, if you decide to be pregnant

Important note:

This document is prepared by the “Mental Health for All” team. The general information provided on the Website is for informational purposes only and is not professional medical advice, diagnosis, treatment, or care, nor is it intended to be a substitute therefore. Always seek the advice of your physician or other qualified health provider properly licensed to practise medicine or general healthcare in your jurisdiction concerning any questions you may have regarding any information obtained from this Website and any medical condition you believe may be relevant to you or to someone else. Never disregard professional medical advice or delay in seeking it because of something you have read on this Website. Always consult with your physician or other qualified healthcare provider before embarking on a new treatment, diet, or fitness program. Information obtained on the Website is not exhaustive and does not cover all diseases, ailments, physical conditions, or their treatment.

Triazolam – TRIAZOLAM®

Brand name

  • TRIAZOLAM®

Drug Class

  • Benzodiazepine Hypnotic

Preparations

  • Triazolam Tablets USP125 mg and 0.25 mg

Indications

  • Symptomatic relief of transient and short-term insomnia in patients who have difficulty falling asleep.

Pharmacology

  • Pharmacokinetics:
    • Half-life: 1.5-5.5 hours
    • Peak plasma time: 2 hours
    • Onset of action: 15-30 min
    • Duration of action: 6-7 hours
    • Metabolism: metabolized via hepatic microsomal oxidation
    • Excretion: primarily in the urine

Metabolism

  • Depresses all level of CNS possibly by increasing membrane permeability to chloride ions, which in turn increase the inhibitory activity of GABA on neuronal excitability.

Dosing

  • Dosage in all patients:
    1. Initial dose: 0.125 mg (immediately before retiring)
    2. Duration: should usually not exceed 7-10 consecutive days.
    3. Max dose: Should not be exceeded 0.25 mg (0.5mg is used only for exceptional patients who do not respond to a trial of the lower dose.)
  • Dosage in elderly or debilitated patients and patients with disturbed liver/kidney function:
    1. Should not exceed 0.125 mg before retiring (0.25 mg is used only for exceptional patients who do not respond to a trial of the lower dose.)

Drug Interactions

  1. alcohol, antihistamines, anticonvulsants, or psychotropic medications: co-administration produces additive CNS depressant effects
  2. Cimetidine, erythromycin: interfere with triazolam metabolism

Adverse Effects

  • Most frequent:
    • Sedation (morning drowsiness, somnolence), dizziness, nervousness, irritability and impaired coordination.
  • Most serious:
    • memory impairment, abnormal thinking, abnormal behavior, confusion, anxiety, and depression
  • Rare:
    • Dysesthesia, paresthesia, dream abnormalities, drug abuse/habituation, drug withdrawal symptoms, hallucinations, muscle tone disorder, tremor, tinnitus, hearing impairment, eye irritation/redness, edema, chest pain, hot/cold flashes, hypertension, syncope, dyspnea, constipation, flatulence, oral irritation, micturition difficulties, dermatitis, diaphoresis, muscular cramps, muscular weakness, malaise, sexual dysfunction, Elevated levels of SGOT, bilirubin, and alkaline phosphatase

Contraindications

  1. Hypersensitivity to this drug or other benzodiazepines.
  2. Paradoxical reactions to alcohol or sedative medications, and history of substance or alcohol abuse.
  3. Pregnancy
  4. Myasthenia Gravis
  5. Uncorrected narrow-angle glaucoma.

Pregnancy and Breastfeeding

  • Pregnancy: category X
  • Lactation: not recommended in nursing mothers

Precautions

  1. Rebound” Insomnia:
    1. On the first or second night after drug discontinuance, total time asleep, and percentage of time spent sleeping frequently might significantly decrease.
  2. Treatment with triazolam should usually not exceed 7-10 consecutive days.
  3. Use in elderly:
    1. Degree of sedation and impairment of psychomotor performance are more pronounced in the elderly.
  4. Use in patients with severe liver disease:
    1. Greater psychomotor impairment than with minimal liver dysfunction.
  5. Over-dosage:
    1. Manifestations: somnolence, confusion, impaired coordination, slurred speech, coma, respiratory depression and apnea.
    2. Treatment: supportive care
    3. Antidote: flumazenil (‘Anexate’), a benzodiazepine antagonist.
  6. Failure of insomnia to remit after 7-10 days of treatment:
    1. Indicate the presence of a primary psychiatric or medical illness.
  7. Worsening of insomnia or the emergence of new abnormalities of thinking or behavior:
    1. Indicate consequence of an unrecognized psychiatric or physical disorder.
  8. Memory disturbance
    1. Anterograde amnesia:
      1. varying severity
      2. dose-related phenomenon
      3. Elderly subjects at a particular risk.
    2. Transient global amnesia and “traveler’s amnesia”:
      1. Unpredictable
      2. Not necessarily dose-related phenomena.
  9. Abnormal thinking and psychotic behavioral changes:
    1. Characterized by decreased inhibition, e.g., aggressiveness or extroversion
    2. Particular caution in patients with a history of violent behavior.
    3. Psychotic behavioral include:
    4. Bizarre behavior, hallucinations, and depersonalization.
    5. Abnormal behaviors are more with chronic use or high doses.
  10. Confusion:
    1. Triazolam affect mental efficiency, e.g., concentration, attention and vigilance.
    2. The risk of confusion is greater in elderly and patients with cerebral impairment.
  11. Anxiety, restlessness:
    1. Increase in daytime anxiety (interdose rebound anxiety) and restlessness
  12. Depression:
    1. Caution in patients with signs or symptoms of depression >>> because Suicidal tendencies e.g., intentional overdose, is more common in these patients,
  13. Complex sleep-related behaviors:
    1. Caution patients about dangerous sleep-related behaviors such as “sleep- driving – patients usually do not remember these events.
    2. Caution in concomitant use with alcohol and other CNS-depressants increase the risk of such behaviors
  14. Severe Anaphylactic and Anaphylactoid Reactions:
    1. Patients should be informed about angioedema
    2. Patients who develop angioedema after treatment with Triazolam should not be re-challenged with the drug.
  15. Drug abuse, dependence and withdrawal:
    1. Withdrawal symptoms:
      1. convulsions, tremor, abdominal and muscle cramps, vomiting, sweating, dysphoria, perceptual disturbances and insomnia
    2. Abrupt discontinuation should be avoided.
    3. Gradual dosage tapering is recommended in any patient taking more than the lowest dose for more than a few weeks.
    4. High risk of dependence:
      1. in patients with a history of alcoholism, drug abuse, or in patients with marked personality disorders
  16. caution in Patients with specific conditions:
    1. Impaired hepatic function,
    2. Impaired renal function,
    3. severe pulmonary insufficiency,
    4. Sleep apnea.
  17. Patients requiring mental alertness:
    1. Patients should be cautioned about:
    2. Engaging in hazardous occupations such as operating machinery or driving a motor vehicle.
    3. Concomitant ingestion of triazolam and alcohol or CNS depressant drugs.
  18. Use in children:
    1. Not recommended in children below the age of 18.
  19. Use in the elderly:
    1. Lowest possible dose should be used >>> elderly patients are susceptible to dose-related adverse effects

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

Flurazepam Hydrochloride – FLURAZEPAM®

Brand name

  • FLURAZEPAM®

Drug Class

  • Benzodiazepine

Preparations

  • Flurazepam Hydrochloride Capsules USP 15 mg and 30 mg

Indications

  • Sleep disturbance:
    • Symptomatic relief of transient and short-term insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings and/or early morning awakening.
    • Treatment should usually not exceed 7-10 consecutive days.

Pharmacology

Pharmacodynamics:

  • Mechanism of action: Long acting benzodiazepine that depresses all level of CNS (e.g. limbic and reticular formation) by increasing activity of GABA.

Metabolism

Pharmacokinetics: 

  • Metabolism: Flurazepam undergoes rapid and pronounced metabolism to two pharmacologically active metabolites via glucuronic acid conjugation
  • Excretion: mainly urine
  • Half-life elimination: 48-120 hours
  • Peak plasma time:5-3 hours
  • Peak plasma concentration: 0.5-4 ng/ml

Dosing

  • Treatment should be as short as possible, and should not exceed 7-10 consecutive days.
  • Dosage should be individualized for maximal beneficial effects.
  • Adults:
    • Usual adult dosage: 30 mg before retiring
  • Elderly and/or Debilitated Patients:
    • Initial recommended dosage: 15 mg

Drug Interactions

1. Produce additive CNS depressant effects when co-administered with:

  • Alcohol,
  • Sedative Antihistamines,
  • Narcotic Analgesics,
  • Anticonvulsants,
  • Psychotropic Medications.

2. Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) enhance the activity of Flurazepam:

  • Cimetidine
  • Erythromycin

Adverse Effects

  • Most Common:
    • Dizziness, drowsiness, lightheadedness, and ataxia.
  • Less Common:
    • headache, heartburn, upset stomach, nausea, vomiting, amnesia, constipation, diarrhea, gastrointestinal pain, nervousness, apprehension, irritability, weakness, palpitations, chest pains, genitourinary complaints
  • Rare symptoms:
    • leukopenia, granulocytopenia, sweating, flushes, difficulty in focusing, blurred vision, faintness, hypotension, shortness of breath, pruritus, skin rash, dry mouth, bitter taste, excessive salivation, anorexia, euphoria, depression, slurred speech, confusion, restlessness, hallucinations, nightmares, numbed emotions, reduced alertness, changes in libido, inappropriate behavior and elevated SGOT, SGPT, total and direct bilirubin, and alkaline phosphatase, Paradoxical reactions such as excitement, stimulation, agitation, aggressiveness, rages, psychoses and hyperactivity.

Contraindications

  1. Hypersensitivity to benzodiazepines or any component of its formulation
  2. Severe impairment of respiratory function (sleep apnea syndrome)
  3. Myasthenia gravis
  4. Severe hepatic insufficiency

Pregnancy and Breastfeeding

  • Pregnancy: category C
  • Lactation: not recommended in nursing mothers.

Precautions

  1. Concomitant use with alcohol: should be used with extreme caution in patients with a history of alcohol abuse.
  2. Elderly:
    1. Inappropriate and heavy sedation in the elderly, may result in accidental events/falls >>> the smallest possible effective dose should be prescribed.
    2. The lowest possible dose (15 mg) should be used in these subjects.
  3. Failure of insomnia remission after 7-10 days: indicate the presence of a primary psychiatric and/or medical illness or the presence of sleep- state misperception.
  4. Worsening of insomnia or the emergence of new abnormalities of thinking or behavior: may be the consequence of an unrecognized psychiatric or physical disorder.
  5. Caution in patients who in the past manifested paradoxical reactions to alcohol and/or sedative medications.
  6. Anterograde amnesia:
    1. in the most common type of memory problem in patients using flurazepam,
    2. dose-related phenomenon,
    3. elderly are high risk group
  7. Transient global amnesia and “traveler’s amnesia”:
    1. Especially in individuals who have taken benzodiazepines, often in the middle of the night, to induce sleep while travelling.
    2. Unpredictable
    3. Not necessarily dose-related phenomena.
  8. Abnormal thinking and psychotic behavioral changes:
    1. Changes characterized by decreased inhibition, e.g., aggressiveness or extroversion
    2. Particular caution in patients with a history of violent behavior and unusual reactions to sedatives including alcohol and the benzodiazepines.
    3. Psychotic behavioral changes include: bizarre behavior, hallucinations, and depersonalization.
  9. Confusion:
    1. The benzodiazepines affect mental efficiency (e.g., concentration, attention and vigilance.)
    2. The risk of confusion is in greater in: elderly, patients with cerebral impairment.
  10. Anxiety & Restlessness: especially daytime anxiety and/or restlessness
  11. Depression: Caution in patients with signs or symptoms of depression because:
    1. Flurazepam could intensify the disease,
    2. There is a potential risk for self-harm (e.g., intentional overdose)
  12. Complex Sleep-related Behaviors:
    1. Complex sleep-related behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported in patients who have taken flurazepam hydrochloride. Other potentially dangerous behaviors have been reported in patients who got out of bed after taking a sedative-hypnotic and were not fully awake, including preparing and eating food, making phone calls, leaving the house, etc. As with “sleep-driving”, patients usually do not remember these events.
  13. Usage of alcohol and other CNS-depressants with flurazepam:
    1. Flurazepam should not to be taken with alcohol.
    2. Caution is needed with concomitant use of other CNS depressant drugs.
  14. Severe Anaphylactic and Anaphylactoid Reactions:
    1. A severe and rare side effect involving the tongue, glottis or larynx
    2. Additional symptoms include dyspnea, throat closing or nausea and vomiting that suggest anaphylaxis.
    3. If angioedema involves the throat, glottis or larynx >>> airway obstruction may occur and be fatal >>> Patients with history of angioedema after treatment should not be re-challenged with the drug.
  15. Flurazepam additive CNS depressant effect:
    1. When co-administered with alcohol, sedative antihistamines, narcotic analgesics, anticonvulsants, or psychotropic medications.
  16. Concomitant use with compounds which inhibit certain hepatic enzymes:
    1. Enhance the activity of benzodiazepines (e.g. Cimetidine or erythromycin)
  17. Drug Abuse Dependence and Withdrawal:
    1. Withdrawal symptoms: convulsions, tremor, abdominal and muscle cramps, vomiting, sweating, dysphoria, perceptual disturbances and insomnia
    2. Gradual dosage tapering schedule is recommended in any patient taking more than the lowest dose for more than a few weeks.
    3. The recommendation for tapering is particularly important in patients with a history of seizures.
    4. The risk of dependence increased in: patients with a history of alcoholism, drug abuse, or in patients with marked personality disorders.
  18. Influence on sleep:
    1. Flurazepam decreases sleep latency and number of awakenings for a consequent increase in total sleep time.
  19. Rebound Insomnia:
    1. A transient syndrome whereby the symptoms that led to treatment with a benzodiazepines recur in an enhanced form, may occur on withdrawal of hypnotic treatment.
  20. Caution in patients with Specific Conditions:
    1. Impaired hepatic and renal function
    2. Compromised respiratory function.
  21. Caution in patients Requiring Mental Alertness:
    1. Because of Flurazepam’s (flurazepam hydrochloride) CNS depressant effect, patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle.
  22. Use in Children: should not be used in children below the age of 15
  23. Laboratory Tests in the case of repeated usage:
    1. periodic blood counts,
    2. liver, and kidney function tests
  24. Overdosage:
    1. Manifestations overdosage include: somnolence, confusion and coma.
    2. Treatment is supportive.
    3. The benzodiazepine antagonist: flumazenil (‘Anexate’), is a specific antidote.

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

Chlordiazepoxide Hydrochloride – Librax® – Libriumv® – Limbitrol®

Brand name

  • Librax®, Librium®, Limbitrol®

Drug Class

  • Benzodiazepines
  • Anxiolytic
  • Sedative

Preparations

Chlordiazepoxide Hydrochloride Capsules:

  • 5 mg, 10 mg, 25 mg

Chlordiazepoxide and Amitriptyline Hydrochloride film-coated Tablets:

  • 5 mg Chlordiazepoxide and 12.5 mg Amitriptyline Hydrochloride
  • 10 mg Chlordiazepoxide and 25 mg Amitriptyline Hydrochloride

Chlordiazepoxide Hydrochloride and Clidinium Bromide Capsules:

  • 5 mg Chlordiazepoxide Hydrochloride and 2.5 mg Clidinium Bromide

Indications

1. Alcohol Withdrawal:

  • Relief of agitation and tremor and prevention or symptomatic relief of delirium tremens and hallucinations associated with acute alcohol withdrawal.

2. Anxiety and Depressive Disorders:

3. Preoperative Anxiolytics:

4. Peptic Ulcer Disease, Irritable Bowel Syndrome, and Acute Enterocolitis

Pharmacology

  • Inhibition of GABA neurotransmitter action in CNS
  • Site and mechanism of action within the CNS: Appear to involve a macromolecular complex that includes GABAA receptors, high-affinity benzodiazepine receptors, and chloride channels.

Metabolism

Absorption

  • Bioavailability: GI tract

Distribution

  • Extent:
    • Widely distributed into body tissues & cross the blood-brain barrier
    • Excrete into milk and crosses the placenta
  • Plasma Protein Binding: highly bound to plasma proteins

Elimination

  • Metabolism: Mainly in the liver
  • Elimination Route: principally in urine
  • Half-life: 5–30 hours

Special Populations

  • Half-lives of chlordiazepoxide is prolonged in:
    • Geriatric patients
    • Patients with liver disease
    • Patients on hemodialysis

Dosing

Pediatric Patients

1. Anxiety Disorders in children ≥6 years of age:

  • Usual dosage: 5 mg 2–4 times daily or 0.5 mg/kg daily or 15 mg/m2 daily in 3 or 4 divided doses.
  • Maximum initial dosage: 10 mg daily

Adults

1. Alcohol Withdrawal:

  • Initial dose: 50-100 mg dose (repeat dose until agitation is controlled)
  • Max dose: 300 mg daily

2. Anxiety and Depressive Disorders:

  • Monotherapy:
    • Maximum initial dose: 10 mg daily
    • Mild to moderate anxiety: 5–10 mg 3 or 4 times daily
    • Severe anxiety: 20–25 mg 3 or 4 times daily
  • Chlordiazepoxide/Amitriptyline Combination Therapy:
    • Initial dose: 30 or 40 mg/75 or 100 mg daily in divided doses.

3. Preoperative Anxiolytic:

  • 5–10 mg 3 or 4 times daily (for several days preceding surgery.)

4. Peptic Ulcer Disease, Irritable Bowel Syndrome, and Acute Enterocolitis:

  • Maintenance dosage: 5 or 10 mg 3 or 4 times daily

Special Populations

  • Hepatic Impairment: Reduce dosage to the smallest effective dosage
  • Renal Impairment: No specific dosage recommendations
  • Geriatric or Debilitated Patients: Reduce initial dosage and use the smallest effective dosage

Drug Interactions

  1. Antacids (aluminum- and magnesium-containing): Possible decrease in rate chlordiazepoxide absorption
  2. Anticoagulants
  3. Cimetidine: Decreased clearance and increased plasma concentrations of chlordiazepoxide
  4. CNS depressants (e.g., alcohol, anticonvulsants, psychotropic drugs, sedatives)
  5. Psychotropic agents: Concomitant use is not recommended.
  6. Disulfiram: Reduce chlordiazepoxide dosage
  7. Levodopa: decreased control of parkinsonian symptoms
  8. Test for pregnancy (Gravindex test): Possible false-positive reaction
  9. Tests for urinary alkaloids: falsely elevated readings
  10. Tests for urinary 17-ketosteroids: falsely elevated or decreased concentrations

Adverse Effects

>10%:

  • Ataxia, drowsiness, memory impairment, sedation, muscle weakness, rash, decreased libido, menstrual disorders, xerostomia, salivation decreased, increased/decreased appetite, weight gain/loss, micturition difficulties

1-10%:

  • Confusion, dizziness, disinhibition, akathisia, dermatitis, hypotension, increased salivation, sexual dysfunction, incontinence, rigidity, tremor, muscle cramps, tinnitus, nasal congestion

Contraindications

  1. Hypersensitivity to chlordiazepoxide, other benzodiazepines, or any ingredient in the formulation.
  2. Acute angle-closure glaucoma

Pregnancy and Breastfeeding

  • Pregnancy: Category D
  • Lactation: not recommended in nursing mothers.

Precautions

1. CNS Effects:

  • Performance of activities requiring mental alertness and physical coordination may be impaired.
  • Concurrent use of other CNS depressants may cause additive or potentiated CNS depression.
  • Paradoxical reactions (e.g., excitement, stimulation, acute rage) reported in psychiatric patients and in hyperactive aggressive children.

2. Fetal/Neonatal Morbidity: Increase risk of congenital malformations in infants of mothers receiving chlordiazepoxide during the first trimester of pregnancy >>> Usage during the first trimester almost always should be avoided.

3. Usage in patients with Psychiatric problems: should not be used in patients with depressive neuroses or psychotic reactions in which anxiety is not prominent.

4. Abuse Potential:

  • Tolerance, psychologic dependence, and physical dependence might occur following prolonged use
  • Patients with a history of drug or alcohol dependence or abuse are at risk of habituation or dependence

5. Withdrawal Syndrome:

  • Abrupt discontinuance may result in symptoms of withdrawal
  • Symptoms may be relieved by tapering the dosage.

6. Suicide possibility: Use with caution in depressed patients; potential for suicidal tendencies.

7. Use of Fixed Combinations: When used in fixed combination with clidinium bromide or amitriptyline hydrochloride, consider the cautions, precautions, and contraindications associated with the concomitant agent.

8. Usage in Porphyria: because of exacerbation of porphyria use with caution

9. Laboratory Testing: Blood dyscrasias (including agranulocytosis), jaundice, and hepatic dysfunction might occur occasionally >>> Monitor blood counts and liver function tests periodically during prolonged therapy.

10. Caution in Pediatric Usage:

  • Not recommended in children <6 years
  • Response of children to CNS drugs is unpredictable >>>initiate therapy at low dosage and increase as required.
  • Monitor hyperactive, aggressive children for paradoxical reactions (e.g., excitement, stimulation, acute rage)

11. Caution in Geriatric Usage: Prolonged elimination of chlordiazepoxide and its metabolites >>> possibility of increased risk of drowsiness, ataxia, and confusion; generally preventable by proper dosage adjustment

12. Hepatic Impairment: Prolonged elimination of chlordiazepoxide and its metabolites >>> Use with caution.

13. Renal Impairment: Use with caution.

14. Alcohol usage: Advice to patients about importance of not consuming alcoholic beverages.

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

Trimipramine – Surmontil®-Trimip®-Tripramine®

Brand name

  • Surmontil®
  • Trimip®
  • Tripramine®

Drug Class

  • Tricyclic Antidepressant

Preparations

    • Trimipramine Tablets BP: 12.5 mg, 25 mg, 50 mg and 100 mg Trimipramine (as maleate)
    • Trimipramine Capsules: 75 mg Trimipramine (as maleate)

Indications

  • Depressive Illness
  • Endogenous Depression

Pharmacology

Mechanism of action:

  • Tricyclic anti-depressant with sedative properties
  • Anti-cholinergic effects
  • Potentiates sympathetic responses by blocking the re-uptake of noradrenaline which has been released by the presynaptic neurones.
  • Quinidine-like effect on the heart and produces ECG and EEG changes.

Metabolism

  • Absorption: GI
  • Metabolism: Hepatic
  • Distribution:
    • Half-Life: 16-40 hr
    • Peak plasma time: 2 hr
    • Bioavailability: 18-63%
    • Protein Binding: 95%
  • Excretion: Urine

Dosing

Initial Dosage:

  • Adults:
    • Initial dose: 75 mg/day in two or three divided doses.
    • Increase in dosage by 25 mg by adding to the late afternoon doses.
    • Optimal dose: 150 mg/day
  • Severely Depressed Patients:
    • Initial dose: 100 mg/day in two or three divided doses
    • Optimal dose:150 to 200 mg/day
    • Max dose: 300 mg/day
  • Elderly or debilitated patients:
    • Test dose: Give 12.5 to 25 mg of the drug and examine the patient sitting and standing to check for orthostatic hypotension after 45 minutes.
    • Initial doses: not more than 50 mg/day in divided doses
    • weekly increase: not more than 25 mg/week
    • Therapeutic dose: 50 to 150 mg/day.
    • Blood pressure and cardiac rhythm must be checked frequently (particularly in patients who have unstable cardiovascular function)

 Maintenance Dosage:

  • Once a satisfactory response has been obtained >>> the dosage should be adjusted to the lowest level required
  • Medication should be continued for the expected duration of the depressive episode in order to minimize the possibility of relapse following clinical improvement.
  • When a maintenance dosage has been established as described above, trimipramine may be administered in a single dose before bedtime provided such a dosage regimen is well tolerated.

Adverse Effects

Behavioural:

  • Drowsiness (mainly during initial therapy), fatigue, excitement, agitation, restlessness, insomnia, shifts to hypomania or mania, activation of latent psychosis, disorientation, confusion, hallucinations, delusions, nightmares, jitteriness, anxiety, giddiness.

Neurological:

  • Seizures, incoordination, ataxia, tremors, dystonia, extrapyramidal symptoms, numbness, tingling, paresthesia of the limbs, peripheral neuropathy, headache, alteration in EEG patterns, tinnitus, slurred speech.

Autonomic:

  • Dry mouth, urinary retention, constipation, paralytic ileus, disturbance of accommodation, blurred vision, precipitation of latent and aggravation of existing glaucoma, mydriasis, vertigo, syncope.

Cardiovascular:

  • Hypotension, hypertension, palpitations, tachycardia, arrhythmias, prolonged conduction time and asystole, heart block, fibrillation, myocardial infarction, stroke and sudden death in patients with cardiovascular disorders. The ECG changes include flattening or inversion of T-waves, depressed S-T segment and bundle branch block.

Endocrine:

  • Changes in libido, weight gain or loss, testicular swelling, gynecomastia and impotence in the male, breast enlargement and galactorrhea in the female, elevation or lowering of blood sugar levels.

Allergic:

  • Skin rash, edema, urticaria, pruritus, and photosensitivity.

Hematologic:

  • Bone marrow depression, including agranulocytosis, leukopenia, eosinophilia, purpura and thrombocytopenia.

Gastrointestinal:

  • Nausea, epigastric distress, heartburn, vomiting, anorexia or increased appetite, stomatitis, peculiar taste, diarrhea.

Miscellaneous:

  • Obstructive jaundice, weakness, urinary frequency, increased perspiration, alopecia, parotid swelling, black tongue.

Withdrawal Symptoms:

  • Abrupt cessation of treatment after prolonged administration may produce nausea, headache, and malaise. These symptoms are not indicative of addiction.

Contraindications

  1. Hypersensitivity
  2. Concomitant use with MAO inhibitors
  3. Narrow Angle Glaucoma
  4. Prostatic Hypertrophy
  5. Myocardial Infarction: during the acute recovery phase
  6. Acute congestive heart failure.

Pregnancy and Breastfeeding

  • Pregnancy: Category C
  • Breast Feeding: Not recommended in nursing mothers

Precautions

  1. Concomitant use with MAOIs:
    1. Should not be administered concomitantly or within 2 weeks of treatment with an MAO inhibitor.
    2. Hyper pyretic crises, severe convulsions and death have occurred in patients receiving MAO inhibitors and tricyclic antidepressants.
  2. Cardiac problems:
    1. Tricyclic antidepressants in high doses, have been reported to produce arrhythmias, sinus tachycardia, and prolongation of conduction time, unexpected death in patients with cardiovascular disorders.
  3. Myocardial infarction and stroke:
    1. Drug should be administered with caution to patients with a history of cardiovascular disease, those with circulatory lability and elderly patients.
  4. Usage in patients receiving thyroid drugs:
    1. Close supervision is required because of the possibility of cardiovascular toxicity.
  5. Usage in daily activity:
    1. Patients should be advised against driving or engaging in activities requiring mental alertness and physical coordination until their response to the drug has been well established.
  6. Usage with Alcohol:
    1. Response to alcohol might be potentiated.
  7. Usage in children:
    1. not recommended for use in children
  8. Usage in seriously depressed patients:
    1. Possibility of Suicide in seriously depressed patients:
      1. Remains until significant remission occurs.
      2. Patients should be closely supervised throughout therapy.
  • Patient should not have access to large quantities of trimipramine.
  1. Usage in patients with psychiatric disorders:
    1. Precipitate psychotic manifestations in schizophrenic patients and hypomanic or manic episodes in manic-depressive patients.
    2. Reduction or discontinuation of the drug, and/or administration of an antipsychotic agent is needed.
  2. Usage in convulsive disorders:
    1. Trimipramine reduces seizure threshold >>> should be administered with caution in patients with a history of convulsive disorders.
    2. Caution in concurrent administration of ECT with trimipramine.
  3. Possibility of Paralytic ileus:
    1. Particularly in the elderly and in hospitalized patients.
  4. Caution in combined usage with:
    1. Drugs acting on the central nervous system
    2. Alcohol
    3. Barbiturates
    4. CNS depressants
  5. Concomitant usage with anticholinergic agents or sympathomimetic drugs:
    1. Block the antihypertensive effects of guanethidine
    2. Careful supervision and adjustment of dosages are required.
  6. Usage in patients with liver diseases:
    1. Caution of usage in patients with impaired liver function or history of hepatic damage or blood dyscrasias.
    2. Periodic blood counts and liver function test should be performed.
  7. Therapeutic response lag:
    1. Occurs at the onset of therapy and last from several days to a few weeks.
    2. Increasing the dosage does not shorten latent period.
  8. Over dose:
    1. Symptoms: Drowsiness, mydriasis, dysarthria, general weakness, excitement, agitation, hyperactive reflexes, muscle spasms and rigidity, hypothermia, hyperpyrexia, vomiting, perspiration, rapid thready pulse, convulsions, severe hypotension, hypertension, tachycardia, disturbances of cardiac conduction, arrhythmia, congestive heart failure, circulatory collapse, respiratory depression and coma.
    2. Treatment: treatment is essentially symptomatic and supportive.

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

Duloxetine Hydrochloride – CYMBALTA®

Brand name

  • CYMBALTA®

Drug Class

  1. Analgesic
  2. Anti-depressant
  3. Anxiolytic

Preparations

  • Delayed Release Capsules 30 mg and 60 mg

Indications

  1. Major Depressive Disorder: (Adults)
  2. Neuropathic Pain Associated with Diabetic Peripheral Neuropathy
  3. Fibromyalgia
  4. Chronic Pain Associated with Osteoarthritis (OA) of the Knee
  5. Generalized Anxiety Disorder (GAD)
  6. Chronic Low Back Pain

Pharmacology

1. Mechanism of action: serotonin and nor-epinephrine re-uptake inhibitor + weakly inhibits dopamine uptake

2. Pharmacodynamic:

  • Effectiveness in the treatment of depression: inhibition of central nervous system (CNS) neuronal uptake of serotonin and norepinephrine
  • Pain inhibitory action: potentiation of descending inhibitory pain pathways within the central nervous system

Metabolism

Absorption:

  • Orally
  • Maximal plasma concentrations: 6 Hours

Distribution:

  • Duloxetine is highly bound (>90%) to proteins in human plasma

Metabolism:

  • Both CYP2D6 and CYP1A2 catalyze

Excretion:

  • 72% in urine & 19% in feces
  • less than 1% remains unchanged in urine.

Dosing

Adults:

  1. Major Depressive Disorder:
    1. Initial dose: 30 mg/day
    2. Maintenance and Max dose: 60 mg/day, Increase within 1-2 weeks. (No benefit more dosage than that)
    3. Therapeutic response is usually seen after 1-4 weeks of treatment
  2. Generalized Anxiety Disorder:
    1. Initial dose: 30 mg/day
    2. Maintenance dose: 60 mg/day, Increase within 1-2 weeks.
    3. Therapeutic response is usually seen after 1-4 weeks of treatment
    4. Max Dose: 120 mg/day
  3. Neuropathic Pain Associated with Diabetic Peripheral Neuropathy:
    1. Initial dose: 30 mg/day
    2. Maintenance dose: 60 mg/day, Increase within 1-2 weeks.
    3. Therapeutic response is usually seen after 1-4 weeks of treatment
    4. Max Dose: 120 mg/day
  4. Fibromyalgia:
    1. Initial dose: 30 mg/day
    2. Maintenance dose: 60 mg/day, Increase within 1-2 weeks.
    3. Therapeutic response is usually seen after 1-4 weeks of treatment
    4. Max Dose: 120 mg/day >>>> higher than 60 mg/day severe & frequent rate of adverse effects.
  5. Chronic Pain Associated with Osteoarthritis of the Knee:
    1. Initial dose: 30 mg/day
    2. Maintenance dose: 60 mg/day, Increase within 1-2 weeks.
    3. Therapeutic response is usually seen after 1-4 weeks of treatment
    4. Max Dose: 120 mg/day

Drug Interactions

  • Triptans (5Ht1 Agonists)
  • Tramadol
  • MAOIs
  • Warfarin, ASA, NSAIDs
  • SSRIs: fluvoxamine – Paroxetine
  • Anti-arrhythmics Flecainide and Encainide
  • John’s wort
  • Thioridazine
  • Tricyclic Antidepressants
  • Medications have highly plasma protein binding affinity
  • Benzodiazepines
  • Smoking

Adverse Effects

More than 10% :

  • Nausea
  • Dry Mouth
  • Headache
  • Somnolence
  • Fatigue
  • Dyspepsia

Less than 10% :

  • Constipation
  • Diarrhea
  • Insomnia
  • Dizziness
  • Anorexia
  • Decreased appetite
  • Akathisia/Psychomotor Restlessness: occur within the first few weeks mostly >>> Decrease the dose
  • Bone Fracture Risk
  • Increases the risk of elevation of serum aminotransferase levels
  • Cardiovascular: Significant hypertension
  • Sedation
  • Dizziness
  • Sexual Dysfunction ( Decreased Libido & Ejaculation dysfunction)
  • Serious Skin Reactions: Stevens-Johnson Syndrome
  • Musculoskeletal pain

Contraindications

  1. Hypersensitivity
  2. Monoamine Oxidase Inhibitors (MAOIs): eg; Antibiotic Linezolid + Thiazine dye methylthioninium chloride (methyleneblue)
  3. Hepatic Impairment
  4. Uncontrolled Narrow-Angle Glaucoma
  5. Severe Renal Impairment: Creatinine clearance <30 mL/min
  6. Thioridazine
  7. CYP1A2 Inhibitors: fluvoxamine & Quinolone antibiotics >>> Ciprofloxacin or Enoxacin
  8. Monoamine Oxidase Inhibitors (MAOIs): within at least 14 days of discontinuing treatment with a MAOI
  9. Hepatic Impairment: CYMBALTA is contraindicated in patients with any liver disease resulting in hepatic impairment
  10. Thioridazine: prolongation of the QTc interval >>> ventricular arrhythmias >>> torsades de pointes >>> sudden death
  11. Sucrose: Patients with:
    1. fructose intolerance,
    2. glucose-galactose malabsorption
    3. sucrose-isomaltase insufficiency

Pregnancy and Breastfeeding

  • Pregnancy: Category C
  • Lactation: Not Recommended in nursing women

Precautions

1. Should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

2. Geriatrics: usage with caution (≥65 years of age)

3. Pediatrics (<18 years of age):

  • May be associated with behavioural and emotional changes >>> increased risk of suicidal ideation

4. Monoamine Oxidase Inhibitors (MAOIs):

  • Not to use within 14 days of discontinuing treatment with a MAOI >>> increase the risk of Neuroleptic Malignant syndrome and Serotonin syndrome

5. Potential Association with Behavioural and Emotional Changes, Including Self-Harm >>> Suicidal / Homicidal ideation.

6. Akathisia/Psychomotor Restlessness:

  • Occur within the first few weeks mostly.

7. Discontinuation Symptoms:

  • Should be discontinued abruptly if:
  • Dizziness, Nausea, Headache, Paresthesia, Fatigue, Vomiting, Irritability, Nightmare, Insomnia, Diarrhea, Anxiety, Hyperhidrosis, Vertigo, Somnolence, & myalgia.

8. Increases the risk of elevation of serum aminotransferase levels:

  • Be aware of the signs and symptoms of liver damage:
  • Pruritus, dark urine, jaundice, right upper quadrant tenderness/ unexplained “flu-like” symptoms >>>> CYMBALTA should be discontinued and should not be restarted in patients with jaundice.

9. Concomitant use with Thioridazine:

  • Prolongation of the QTc interval >>> ventricular arrhythmias >>> torsade de pointes >>> sudden death

10. CYMBALTA capsules contain sucrose:

  • Patients fructose intolerance, glucose-galactose malabsorption / sucrose-isomaltase insufficiency >>> should not take this medicine.

11. Bone Fracture Risk:

  • Elderly patients & patients with important risk factors for bone fractures: >>> should be advised of possible adverse events which increase the risk of falls:
  • Dizziness and orthostatic hypotension, especially at the early stages of treatment & soon after withdrawal.

12. Cardiovascular:

  • Might increase in blood pressure & clinically significant hypertension (Cause: noradrenergic effect):
  • Use with caution in patients with uncontrolled hypertension
  • Blood pressure & heart rate should be evaluated prior to initiating treatment & throughout treatment.

13. Diabetic gastroparesis:

  • Caution should be exercised in using CYMBALTA in patients with conditions that slow gastric emptying like Diabetic gastroparesis.

14. Dependence Liability:

  • Carefully evaluate patients for a history of drug abuse & follow them closely:
  • Duloxetine abuse/misuse>>> Drug seeking behaviours

15. Glycemic control:

  • CYMBALTA treatment may worsen glycemic control in diabetic patients >>> HbA1C may increase by 0.5%.

16. Abnormal Bleeding:

  • SNRIs, including CYMBALTA, may increase the risk of bleeding events >>> abnormal platelet aggregation:
  • Caution in concomitant use with ASA, Warfarin & NSAIDs

17. Reversible Hyponatremia:

  • May be the result of Syndrome of Inappropriate ADH (SIADH) >>> Discontinue in symptomatic patients.

18. Seizure:

  • Used with caution in patients with a history of a seizure disorder.

19. Avoid driving and / Using Machines:

  • Because of psychomotor impairment effect

20. Activation of Mania/Hypomania:

  • Should be used cautiously >>> May be at an increased risk of experiencing manic episodes when treated with antidepressants alone!

21. Urinary Hesitation and Retention:

  • Caution in patients who use concomitant medications that may affect voiding (e.g., anticholinergics)

22. Patients With Substantial Alcohol Use:

  • May be associated with severe liver injury.

23. Medications have highly plasma protein binding affinity:

  • Duloxetine is highly bound to plasma proteins (>90%) >>> Increased free plasma concentration of either drugs.

24. Benzodiazepines:

  • Concomitant use >>> Increased Sedation effect. Use with caution!

25. Smoking:

  • Bioavailability appears to be about 34% lower in smokers than in non-smokers >>> Dose adjustment not routinely recommended.

26. Administration:

  • May be administered with or without food >>>> food may help reduce the incidence of initial nausea.

27. CYMBALTA should be swallowed whole and should not be chewed or crushed.

28. Overdose:

  • No specific antidote >>> Supportive therapy.

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

Amitriptyline Hydrochloride – ELAVIL®

Brand name

  • ELAVIL®

Drug Class

  • Tricyclic Antidepressant

Preparations

  • Tablets USP 10, 25, 50 and 75 mg

Indications

  1. Depressive Illness
  2. Depressive Illness of Psychotic or Endogenous Nature
  3. Neurotic Depression
  4. Anxiety Component of Depression

Pharmacology

  • Inhibits the membrane pump mechanism responsible for the re-uptake of transmitter amines
  • Drug has anticholinergic properties, so it produces EKG changes and quinidine-like effects on the heart

Metabolism

Absorption:

  • peak serum time: 4 hours
  • Orally administered drugs is readily absorbed and rapidly metabolized.

Metabolism:

  • Metabolized by hepatic CYP2C19, CYP3A4
  • Metabolite: Nortriptyline

Elimination:

  • Half-life: 9-27 hours

Excretion:

  • Major in the urine, with some excretion in the feces.

Dosing

Initial Dosage:

  • Outpatient Adults:
    • Initial dose: 25 mg 3 times a day.
    • Max dose: 150 mg/day.
    • Increases should made preferably in the late afternoon or bedtime doses.
  • Severely ill or hospitalized patients:
    • Initial dose: 100 mg a day
    • Max dose: 200 mg a day (Small number of hospitalized patients may need 300 mg a day)
  • Adolescent and Elderly Patients:
    • Lower dosages are recommended.
    • The dose should be administered in divided doses or as a single dose in the evening or at bedtime.

Maintenance:

  • When satisfactory improvement has been reached, dosage should be reduced to the lowest amount that will maintain relief of symptoms.
  • Usual maintenance dose: 50 to 100 mg/day in divided doses
  • In suitable patients, the total daily dosage may be given in a single dose, preferably at bedtime.

Drug Interactions

  1. Guanethidine or similarly acting compounds
  2. Anticholinergic or sympathomimetic drugs (including epinephrine combined with local anesthetics)
  3. Cimetidine
  4. Ethchlorvynol
  5. Alcohol, barbiturates and other CNS depressants
  6. Disulfiram
  7. Anticholinergic agents or with neuroleptic drugs

Adverse Effects

Behavioral:

  • drowsiness, fatigue, activation of latent schizophrenia, disorientation, confusional states, hallucinations, delusions, hypomanic reactions, disturbed concentration, nightmares, insomnia, restlessness, agitation, excitement, jitteriness, anxiety, giddiness.

Neurological:

  • epileptiform seizures, coma, dizziness, tremors, numbness, tingling, parasthesias of the extremities, peripheral neuropathy, headache, ataxia, alteration in EEG patterns, extrapyramidal symptoms including abnormal involuntary movements and tardive dyskinesia, dysarthria, tinnitus, incoordination, and slurred speech.

Anticholinergic:

  • Urinary retention, dilatation of the urinary tract, constipation, paralytic ileus, especially in the elderly, hyperpyrexia, dry mouth, blurred vision, disturbance of accommodation, increased intraocular pressure, precipitation of latent glaucoma, aggravation of existing glaucoma, and mydriasis.

Cardiovascular:

  • quinidine-like effect and other non-specific ECG changes and changes in AV conduction, prolonged conduction time, asystole, hypotension, syncope, hypertension, palpitation, arrhythmias, heart block, ventricular tachycardia, fibrillation, myocardial infarction, stroke, unexpected death in patients with cardiovascular disorders.

Hematologic:

  • Bone marrow depression, including agranulocytosis, leukopenia, eosinophilia, purpura, thrombocytopenia.

Allergic:

  • Skin rash, urticaria, photosensitization, edema of the face and tongue, itching. Gastrointestinal: nausea, epigastric distress, heartburn, vomiting, hepatitis (including altered liver function and jaundice), anorexia, stomatitis, peculiar taste, diarrhea, parotid swelling, black tongue may occur.

Endocrine:

  • Testicular swelling, gynecomastia and impotence in the male, breast enlargement and galactorrhea in the female, increased or decreased libido, elevation and lowering of blood sugar levels, syndrome of inappropriate ADH (antidiuretic hormone) secretion.

Miscellaneous:

  • Weakness, increased perspiration, edema, urinary frequency, alopecia, increased appetite, weight gain, weight loss.

Withdrawal Symptoms (following abrupt cessation):

  • Nausea, headache, and malaise, irritability, restlessness, and dream and sleep disturbance. These symptoms are not indicative of addiction.

Contraindications

  • Hypersensitivity
  • MAO inhibitors
  • Myocardial infarction (during the acute recovery phase following MI)
  • Acute congestive heart failure

Pregnancy and Breastfeeding

  • Pregnancy: Category C
  • Lactation: Not recommended in nursing mothers

Precautions

  1. Caution in patients with a history of:
    • Seizures,
    • Impaired Liver Function,
    • Hepatic Damage,
    • Blood Dyscrasias,
    • cardiovascular disease (myocardial infarction & congestive heart failure)
  2. Atropine-like action: caution in patients with a history of:
    • urinary retention,
    • narrow-angle glaucoma
    • Increased intra-ocular pressure.
  3. Fatal Dysrhythmia:
    • Occurring as late as 56 hours after amitriptyline overdose.
  4. Cardiovascular disorders and Stroke:
    • Caution in concurrent usage >>> Patients should be watched closely.
    • TCA drugs produce arrhythmias, sinus tachycardia, and prolongation of the conduction time.
  5. Electroshock Therapy:
    • Concurrent administration increase the hazards of therapy >>> treatment should be limited to the specific patients
  6. Hyperthyroid Patients:
    • Close supervision is required
  7. Occupational Hazards:
    • Impair mental and/or physical abilities required for performance of hazardous tasks >>> caution in operating machinery or driving a motor vehicle.
  8. Children:
    • Not recommended for patients under 12 years of age.
  9. Treatment of depressive component of schizophrenia:
    • Activation or aggravation of existing psychotic manifestation may occur.
  10. Seriously depressed patients:
    • Should be carefully supervised.
    • The possibility of suicide remains during treatment.
    • Patients should not have access to large quantities of drug during treatment.
  11. Elective Surgery:
    • Discontinue the drug several days before surgery
  12. MAO Inhibitors:
    • Concomitant usage with MAO inhibitors result in: Hyper-pyretic crises, severe convulsions, and deaths
    • Minimum of 14 days elapse is needed.
  13. Myocardial Infarction & Congestive Heart Failure:
    • Not recommended for use during the acute recovery phase following myocardial infarction and in the presence of acute congestive heart failure.
  14. EEG & Sleep Patterns:
    • It also lowers the convulsive threshold and causes alterations in EEG and sleep patterns.
  15. Guanethidine or Similarly Acting Compounds:
    • Amitriptyline block the anti-hypertensive action of Guanethidine.
  16. Anticholinergic or sympathomimetic drugs (including epinephrine combined with local anesthetics):
    • Concomitant usage needs close supervision and adjustment of dosage.
    • Paralytic ileus: appropriate measures should be taken if constipation occurs.
  17. Cimetidine:
    • Reduce hepatic metabolism of tricyclic antidepressants.
  18. Ethchlorvynol:
    • Concomitant usage result in transient delirium: Caution if patients is receiving large doses of Ethchlorvynol.
  19. Alcohol, barbiturates and other CNS depressants:
    • Amitriptyline enhances the response to alcohol and the effects of barbiturates and CNS depressants.
  20. Disulfiram:
    • Caution Delirium has been reported with concurrent administration of amitriptyline and disulfiram.
  21. Anticholinergic agents or with neuroleptic drugs:
    • Hyperpyrexia has been reported when tricyclic antidepressants are administered with anticholinergic agents or with neuroleptic drugs.
  22. Over dosage:
    • Symptoms: temporary confusion, disturbed concentration, transient visual hallucinations, drowsiness, hypothermia, tachycardia, arrhythmic abnormalities, such as bundle branch block, ECG evidence of impaired conduction, congestive heart failure, disorders of ocular motility, convulsions, severe hypotension, stupor, coma, polyradiculoneuropathy and constipation.
    • Treatment:
      • Treatment is symptomatic and supportive.
      • Patients who may have ingested an over dosage of amitriptyline, particularly children, should be hospitalized and kept under close surveillance.

Section

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

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