Anti-Depression Drugs PDF

Anti-depression drugs  1. TCAs Tertiary Amines Amitriptyline Doxepin Imipramine Clomipramine Trimipramine  1. TCAs Secondary Amines Desipramine Nortriptyline Protriptylene Amoxapine Maprotiline ...

Anti-depression drugs  1. TCAs Tertiary Amines Amitriptyline Doxepin Imipramine Clomipramine Trimipramine  1. TCAs Secondary Amines Desipramine Nortriptyline Protriptylene Amoxapine Maprotiline  1. TCAs Mechanism of action:  Reuptake inhibition of neurotransmitter  GABAergic system / Inhibit the influx of chloride  Sodium channel block  Cholinergic receptor block  Antihistaminic effects  α blocker  1. TCAs Pharmacokinetics  Drug absorption : rapid  Peak serum concentrations : 2-6 hr  Highly lipophilic / large volume of distribution  Highly protein bound  Serum PH  Elimination is almost entirely hepatic  Half-life of elimination for therapeutic doses : 8 to 30 hr 1. TCAs  1. TCAs  The most severe toxicities from CA overdose :  Hypotension  Dysrhythmia  Coma  Seizures  Hyperthermia  1. TCAs  Cardiovascular System Toxicity: 1. TCAs  1. TCAs  QRS interval prolongation  The QRS axis is typically shifted to the right  Increase in the R wave amplitude in aVR  Deep S wave in lead I or aVL  1. TCAs  Negative inotropy and vascular smooth muscle effect  CAs inhibit the influx of calcium into cardiac and neural tissue and interfere with calcium-coupled muscular contraction  Dysrhythmias :  Sinus tachycardia  Ventricular tachycardia (VT)  Torsades de pointes (TdP)  1. TCAs  Central Nervous System Toxicity  CNS depression  Seizures  Other neurologic symptoms include delirium and myoclonus  Urinary retention, ileus, and dry skin  Pulmonary complications include aspiration pneumonitis and adult respiratory distress syndrome  Hyperthermia  1. TCAs  Therapeutic CA concentrations are generally in the range of 50 to 300 ng/mL.  Life-threatening toxicity : serum concentration of greater than 100 ng/mL, while concentrations greater than 300 to 500 ng/mL are often fatal.  Measurement of serum electrolytes, blood urea nitrogen, creatinine, creatine kinase, hematocrit, and liver function tests.  Arterial blood gas (ABG)  1. TCAs  MANAGEMENT  Supportive Measures  activated charcoal  NaHCO3  PHENYTOIN  TCA ANTIBODIES  α1-ACID GLYCOPROTEIN  PHYSOSTIGMINE 2. SSRIs and Atypical Antidepressants  2. SSRIs and Atypical Antidepressants  Absorption / FPE  Effect of food  Peak concentration averages 4 to 8 hours  Highly protein bound  Volume of distribution is large  The elimination half-life varies considerably among the various agents, ranging from 2 to 4 hours for nefazodone to 48 to 96 hours for fluoxetine  2. SSRIs and Atypical Antidepressants  The Elderly  Patients with Renal and Hepatic Disease (Paroxetine/ mirtazapine)  Pregnant and Lactating Patients (fluoxetine / paroxetine, sertraline, or fluoxetine)  Children and Adolescents  2. SSRIs and Atypical Antidepressants  DRUG INTERACTIONS : 1. Serotonin syndrome 2. Inhibition of the CYP450 system  2. SSRIs and Atypical Antidepressants  minor symptoms drowsiness, tremor, weakness, nausea, and vomiting.  Seizures  Electrocardiographic (ECG) changes  Death  2. SSRIs and Atypical Antidepressants  Acute overdose :  Drowsiness, nausea, and vomiting  Dizziness, headache, tremor, and agitation  Dysrhythmias and seizures  Serotonin syndrome 2. SSRIs and Atypical Antidepressants  2. SSRIs and Atypical Antidepressants  MANAGEMENT  Supportive measures  Activated charcoal / whole bowel irrigation  There are no specific antidotes  Bicarbonate 3. Monoamine Oxidase Inhibitors (MAOIs)  3. Monoamine Oxidase Inhibitors (MAOIs)  Phenelzine (NARDIL)  Tranylcypromine (PARNATE)  Isocarboxazid (MARPLAN)  Selegiline (ELDEPRYL)  3. Monoamine Oxidase Inhibitors (MAOIs)  rapidly and completely absorbed  peak plasma concentrations ranging from 1 to 4 hours  hepatic metabolism  half-lives range from 1 to 3 hours  plasma drug concentrations do not correlate with the level of MAO inhibition  RIMAs 3. Monoamine Oxidase Inhibitors (MAOIs) 3. Monoamine Oxidase Inhibitors (MAOIs) 3. Monoamine Oxidase Inhibitors (MAOIs)  3. Monoamine Oxidase Inhibitors (MAOIs)  severe toxic syndrome  Approximately 2 mg / kg : Threatening potential life  Four steps: 1. Asymptomatic / 6 -12 hr 2. Neuromuscular excitation and sympathetic hyperactivity /sympathomimetic syndrome:  Neuromuscular excitation  Sympathic hyperactivity  3. Monoamine Oxidase Inhibitors (MAOIs)  3. Central nervous system (CNS) depression with the potential for cardiovascular collapse  4. Secondary complications for survivors of the above  3. Monoamine Oxidase Inhibitors (MAOIs)  TREATMENT  There are no specific antidotes  Phentolamine  Barbiturates / Benzodiazepine  Vit B6  ICU  Activated charcoal  3. Monoamine Oxidase Inhibitors (MAOIs) Serotonin Syndrome  Cognitive-Behavioral Symptoms : Confusion/disorientation, Agitation/irritability, Anxiety, Coma  Autonomic Nervous System: Hyperthermia, Diaphoresis, Sinus tachycardia, Hypertension, Dilated pupils, Flushing  Neuromuscular : Myoclonus, Hyperreflexia, Muscle rigidity, Restlessness/hyperactivity, Tremor, Ataxia 3. Monoamine Oxidase Inhibitors (MAOIs) 3. Monoamine Oxidase Inhibitors (MAOIs)  Cooling a patient  Benzodiazepine  Muscle Relaxants  Cyproheptadine  Sedative-Hypnotics Poisoning Sedative-hypnotic is a term that describes different medications that sedate or calm a person or induce drowsiness and sleep. Chloral hydrate : 1832 Barbital :1903 Phenobarbital : 1912 Chlorpromazine : 1950s  INTRODUCTION AND HISTORY High abuse potential Tolerance Acute toxicity During the 1980s to 1990s, selective benzodiazepine receptor agonists (zolpidem, zaleplon, zopiclone (not available in the United States), and zolpidem).  Mechanism of action Exact mechanism of action : unknown or unclear Some affect the γ-aminobutyric acid (GABA) chloride channel.  Mechanism of action Chloral hydrate Trichloroethanol (TCE) GABAA receptor–ion channel  Altering chloride currents and decreasing excitability of neurons  Inhibits ion currents activated by excitatory amino acids  Sensitizes the myocardium to endogenous catecholamines Chlormethiazole GABAA-evoked currents At low doses it potentiates GABA evoked responses At high doses it directly activates the GABA receptor  Prolongs the GABA channel burst duration  Potentiates glycine-evoked currents  Mechanism of action Meprobamate GABAA receptor–ion channel Potentiates GABA at the GABAA receptors and also activates the chloride channel in the absence of GABA Zaleplon, zolpidem, and zopiclone GABAA benzodiazepine receptor agonists  ethchlorvynol, glutethimide, and methyprylon unknown Glutethimide 4-hydroxy-2-ethyl-2-phenylglutarimide  General Pharmacology and Pharmacokinetics Absorption varies greatly between the sedative-hypnotic agents Some have significant first pass clearance Initial plasma elimination Later slow elimination All are extensively metabolized in the liver  General Toxicology Overdose : sedation, dizziness, hypothermia, and hypotension that can progress to coma and respiratory depression Patients may vomit and aspirate, leading to pneumonia or even death Adverse Effects : o Physical dependence and cross-tolerance o Withdrawal symptoms have been reported after chronic use and abuse  Chloral Hydrate/Trichloroethanol Rapid reduction to TCE. Half-life TCE 7-11 hr (avg 8 hr) Renal Excretion : Less than 10% parent compound Metabolism : Liver Protein Binding : 70%–80% Peak : 0.3- 1 hr  Chloral Hydrate/Trichloroethanol Special Populations : neonates / accumulation and persistence of TCE TCE competes with bilirubin DRUG INTERACTIONS:  Ethanol : Competition for alcohol dehydrogenase system/ Accumulation of trichloroethanol and elevated ethanol levels (Mickey Finn) Furosemide : Displacement of furosemide from protein binding sites/ Cardiovascular toxicity  Warfarin : Displacement of Warfarin from protein binding sites/ Increased risk of bleeding  Chloral Hydrate/Trichloroethanol Cardiac toxicity: Atrial and ventricular dysrhythmias : unifocal and multifocal ventricular premature contractions, bigeminy, torsades de pointes, ventricular fibrillation, and asystole Ethanol and chloral hydrate : CNS depressant actions of both are enhanced, leading to the so-called knock-out drop / decreased level of consciousness vasodilation, tachycardia, facial flushing, headache, and hypotension  Chlormethiazole In patients with cirrhosis that co-ingested with alcohol /10-fold increase in bioavailability/ impaired first pass effect  Low serum albumin in alcoholics leads to decreased protein binding, allowing for an increased free drug serum concentration. DRUG INTERACTIONS :  Ethanol and imipramine : additive clinical effects TOXICOLOGY : coma : 40 to 92 hours Increased salivation and bronchial secretions  Chlormezanone Chlormezanone is rapidly absorbed and metabolized into at least six compounds, which are excreted in the urine.  The volume of distribution : 85 L  The half-life following an overdose : 29-35 hr. Chlormezanone is similar to baclofen in chemical structure / muscle relaxant effect In elderly patients : oral absorption of chlormezanone was delayed but not reduced DRUG INTERACTIONS :  Ethanol and imipramine : additive clinical effects  Chlormezanone Metabolic acidosis  Hepatitis may occur (elevation of liver enzymes, prolonged prothrombin time, elevated bilirubin, and hypoglycemia) Central anticholinergic syndrome /combination with ofloxacin and diphenhydramine ADVERSE EFFECTS :  Even with the recommended dose of chlormezanone, a hypersensitivity reaction can result in a transient hepatitis, which is associated with eosinophilia, cholestasis, and mild periportal infiltration.  Fixed skin eruption  Glutethimide Intoxication with glutethimide results in a prolonged coma with variations in coma depth and sudden apnea Cerebral edema and seizures Acute renal failure is rare but has been reported Anticholinergic activity (reduced gastric motility and delayed gastrointestinal transit, urinary retention, mydriasis, and some of the hallucinations and delusions )  In the 1970s, there were reports of neonatal withdrawal from glutethimide  Meprobamate Meprobamate has a low solubility in water, is resistant to gastric and intestinal juices  Bezoar formation The metabolism of meprobamate is induced by ethanol Elimination might be increased by hemoperfusion Carisoprodol is a muscle relaxant (half-life of 100 minutes) that is converted to meprobamate (half-life of 11.3 hours). DRUG INTERACTIONS :  Ethanol and imipramine : additive clinical effects  Meprobamate Meprobamate intoxication may be difficult to distinguish from other sedatives Cardiac dysrhythmias include both tachycardia and bradycardia; hypotension coma and seizures Pulmonary edema skin lesions Meprobamate deaths have been attributable to shock, pulmonary edema, or complications such as pneumonia or sepsis  Methyprylon Methyprylon is structurally and pharmacologically related to glutethimide Nearly complete gastrointestinal absorption Hepatic metabolism is via the P-450 dehydrogenase system The elimination half-lives of methyprylon (4 to 50 hours). DRUG INTERACTIONS :  Ethanol and imipramine : additive clinical effects  Methyprylon Patients with methyprylon overdose may demonstrate inconsistent findings : No hypotension, moderate to severe hypotension / no decrease in peripheral reflexes  hyperreflexia and seizure activity, hyper reflexia and areflexia, pinpoint, sluggish pupils, or fixed and dilated pupils supportive treatment plus hemodialysis  Zaleplon, Zolpidem, and Zopiclone Zaleplon has a more rapid elimination than zolpidem Zolpidem has a rapid absorption, rapid distribution into the CNS, and rapid onset of activity. zolpidem is metabolized in the liver by four different P-450 pathways: 61% 3A4 22% 2C9 14% 1A2 Less than 3% 2D6 , 2C19 Zopiclone has a high bioavailability low volume of distribution  Zaleplon, Zolpidem, and Zopiclone Rifampin, phenytoin and carbamazepine : resulting in decreased maximum peak concentration and increased total clearance. imipramine, paroxetine, or thioridazine with Zaleplon : additive psychomotor effects Cimetidine with zaleplon Erythromycin with zopiclone The half-life of zolpidem is reduced by smoking and oral contraceptive use  Decreased psychomotor performance has been observed with the combination of chlorpromazine and zolpidem An increased risk for hallucinations : bupropion, fluoxetine, sertraline, venlafaxine, and desipramine.  Zaleplon, Zolpidem, and Zopiclone drowsiness and vomiting gait abnormalities, blurred vision, mydriasis, visual hallucinations, and memory impairment respiratory depression or failure and hypotension ADVERSE EFFECTS : Withdrawal symptoms Hallucinations Amnesic psychotic reactions and agitation  DIAGNOSIS complete blood count, serum electrolytes, blood urea nitrogen (BUN), creatinine, liver enzymes, and arterial blood gas Therapeutic serum chlormezanone levels are normally 4 to 6 mg/L, with levels greater than 50 mg/L considered toxic. Meprobamate levels of 3 to 10 mg/dL are associated with mild to moderate signs of toxicity, 10 to 20 mg/dL with deeper coma, and greater than 20 mg/dL with severe toxicity and increased fatality rate. Methaqualone levels of 2 to 5 μg/dL are generally considered to be in the toxic range Methyprylon levels of greater than 3.0 mg/dL are associated with coma, and levels less than 3.0 mg/dL are generally associated with somnolence.  DIAGNOSIS electrocardiography (ECG) and chest radiography Chloral hydrate is radiopaque Methaqualone ECG abnormalities : right bundle branch block and nonspecific T wave abnormalities  Supportive Measures For comatose patients: airway, ventilation, and cardiovascular system Hypotension may be treated with isotonic fluid boluses; vasopressors and inotropes should be used as indicated Cardiac dysrhythmias should be treated according to advanced cardiac life support (ACLS) protocols Seizures may be treated with benzodiazepines  Normal body temperature should be maintained  Decontamination Gastric lavage Activated charcoal 1 g/kg Multiple-dose activated charcoal Whole bowel irrigation  There are no specific antidotes currently available for sedative-hypnotic overdoses. Naloxone and Flumazenil may precipitate ventricular dysrhythmias Propranolol (adults 1.0 to 2.0 mg IV bolus followed by 1.0 to 2.0 mg/hr infusion, children 0.01 to 0.1 mg/kg, maximum 1 mg) Esmolol (adults 500 μg/kg IV slow bolus over 2 minutes followed by 25 to 100 μg/kg/min, children 100 to 500 μg/kg given over 1 minute, followed by infusion of 25 to 100 μg/kg/min, titrated to dysrhythmias cessation) Torsades de points may be treated with IV magnesium or overdrive pacing. Platelets, fresh frozen plasma, and vitamin K should be administered for uncontrolled bleeding after methaqualone ingestion.  Elimination Enhancement Hemodialysis Hemoperfusion Osmotic diuresis Barbiturates  Barbiturates Barbiturates bind to γ-aminobutyric acid A [GABAA] / mediates fast synaptic transmission Enhanced GABA effects  Barbiturates Anticonvulsant hypersensitivity syndrome (AHS): life-threatening phenobarbital and primidone 1to 8 weeks after initiation fever, cervical adenopathy, pharyngitis, skin findings ranging from skin eruption to Stevens-Johnson syndrome, and systemic injury Glucocorticoids, steroids, IgG(IV)  Barbiturates TOXICITY (1) mild intoxication (victims are somnolent but arousable with slurred speech, unsteady gait, and nystagmus) (2) moderate intoxication (victims have depressed level of consciousness, decreased deep tendon reflexes, and slowed respirations) (3) severe intoxication (victims are unresponsive to painful stimuli; respiratory, cardiovascular, and neurologic collapse occur).  Barbiturates Coma blisters Barbiturates  Barbiturates EVALUATION AND MANAGEMENT Supportive Measures Activated charcoal / gastric lavage / Multiple-dose activated charcoal (MDAC) Urine alkalinization : pKa of 7.4, phenobarbital Hemodialysis /phenobarbital The therapeutic range for phenobarbital is generally considered 15 to 40 μg/mL. Toxic effects from phenobarbital can be seen at 50 μg/mL  Barbiturates One of the potential common drug interactions with barbiturates occurs when they are given in conjunction with other sedative-hypnotics. Benzodiazepines, alcohol, anesthetics such as propofol and etomidate, glutethimide, and zolpidem. Thujonecontaining herbs such as wormwood and sage, and gamolenic acid– containing herbs such as evening primrose oil and borage.  Benzodiazepines Chlordiazepoxide 1955 sedative, hypnotic, amnestic, anxiolytic, anticonvulsant, and muscle relaxant properties All benzodiazepines are effective in the treatment of anxiety and insomnia  Benzodiazepines potentiate the activity of γ-aminobutyric acid (GABA) GABAA increasing the frequency of channel opening  Benzodiazepines Alprazolam Diazepam Clonazepam Triazolam Lorazepam And ….. Benzodiazepines  Benzodiazepines physiologic pH : highly lipid-soluble absorbed from the proximal small bowel Highly lipophilic: diazepam and flurazepam less lipophilic : oxazepam and temazepam co-ingestion of ethanol co-ingestion of food or antacids highly protein bound Benzodiazepines  Benzodiazepines TOXICITY Acute / chronic The acute clinical manifestations of benzodiazepines are mainly those of CNS depression. mild to moderate sedation, often with dysarthria and ataxia, without serious neurologic, cardiovascular, or respiratory impairment.  Benzodiazepines Supportive Measures Antagonist GABAA : Flumazenil Activated charcoal  Benzodiazepines Withdrawal Syndrome Panic attacks Anxiety Hypersensitivity to stimuli like light and touch Insomnia Abnormal bodily sensations (skin-crawling, Irritability goosebumps) Restlessness Depression Hand tremors Problems with memory Muscle spasms Visual disturbances (flashes of light or blurred vision) Headache Auditory, tactile, or visual hallucinations Sweating Feelings of unreality Racing pulse Delirium Hyperventilation Grand mal seizures Nausea or vomiting Aches and pains  Benzodiazepines Benzodiazepine use in pregnancy may be associated with teratogenic effects and fetal loss. Fetal benzodiazepine dependence and subsequent neonatal withdrawal can occur: Hypertonicity Irritability Tremors Hyperreflexia Tachypnea Weight loss