Anti- Depressant

1. Anti- Depressant Dr. Hayder B Sahib PhD Pharmacology

2. Antidepressants • Major depression is one of the affective disorders, and is perhaps the commonest mental illness worldwide. • It is characterized by • 1- feelings of intense sadness • 2- despair • 3- slowing of thought process • 4- impaired concentration • 5- constant worry • 6- agitation • 7- self-criticism.

3.  Norepinephrine (or noradrenaline) reuptake inhibitors •  a. Tertiary amine tricyclics: amitryptiline, clomipramine, doxepin, imipramine, trimipramine. •  b. Secondary amine tricyclics: amoxapine, desipramine, maprotiline, nortriptyline, protriptyline.

4.  Selective serotonin reuptake inhibitors  Citalopram, duloxetine, fluoxetine, fluvoxamine, milnacipran, oxaflozane, paroxetine, pizotifen, sertraline, venlafaxine. •  Monoamine oxidase inhibitors  Isocarboxacid, iproniazid, moclobemide, pargyline, phenelzine, pimozide, selegiline, toloxatone, tranylcypromine. •  Atypical antidepressants  Bupropion, mirtazepine, nefazodone, trazodone.

5.  Cyclic Antidepressants • Tricyclic antidepressants possess a 3-ring molecular structure. Examples include amitriptyline, clomipramine, desipramine, dibenzepin, doxepin, dothiepin, imipramine, lofepramine, ortriptyline, protriptyline and trimipramine. • Uses Tricyclic antidepressants are used to treat a wide range of disorders such as • 1- depression • 2- panic disorder • 3- social phobia • 4- bulimia • 5- narcolepsy • 6- attention deficit disorder • 7- obsessive compulsive disorder • 8- childhood enuresis • 9- chronic pain syndromes.

6. Toxicokinetics  All cyclic antidepressants are rapidly absorbed from the GI tract and have large volumes of distribution (10 to 50 L/kg). • Most of them bind to plasma protein alpha1-glycoprotein with varying affinity. •  They are all highly lipophilic, sparingly water soluble, and substantially metabolized by first-pass in the liver. • The metabolites retain significant pharmacologic activity until hydroxylation occurs by microsomal enzyme system. •  The half-lives of these compounds are highly variable (4 hrs to 93 hrs).

7. Approximately 30% of the absorbed dose is eliminated by gastric and biliary secretion, while renal clearance accounts for 3 to 10% of the parent compound. • It is however important to remember that cyclic antidepressants taken in large quantities (overdose) exhibit significantly altered toxicokinetics. • - Absorption may be delayed by inhibition of gastric emptying and peristalsis. • - Enterohepatic recirculation delays final elimination of a large amount of the drug. • .

8. - Enzymes responsible for hydroxylation can become saturated. • - The amount of drug unbound to plasma proteins may increase (because of acidaemia). •  Following absorption, these agents are extensively bound to plasma proteins and also bind to tissue and cellular sites, including the mitochondria

9. Mode of Action •  Cyclic antidepressants, notably the tricyclics, are structurally similar to the phenothiazines with similar anticholinergic, adrenergic, and alpha-blocking properties of the phenothiazines. •  Cyclic antidepressants act by: - • 1- inhibiting voltage-gated sodium channels in myocardial cells, • 2- blocking of H1, H2, and D2 receptors, as well as muscarinic receptors • 3 - inhibiting alpha-adrenergic receptors • 4- interacting with GABA receptors, • 5 - Inhibiting the transport and reuptake of biogenic amines at nerve terminals.

10.  The toxicity of cyclic antidepressants is mainly due to effects on myocardium, CNS, and peripheral vasculature. • There is prolongation of action potential duration in most myocardial cells, decreased peripheral vascular resistance, and induction of anticholinergic effects. • Convulsions resulting from overdose are caused by complicated interactions within the brain due to altered concentrations of GABA, dopamine, noradrenaline and acetylcholine.

11. Adverse Effects • 1- Postural hypotension • 2- cardiac arrhythmias • 3- vertigo • 4- weakness • 5- tremor • 6- confusion • 7- weight gain • 8- agranulocytosis and thrombocytopenia. •  Anticholinergic effects are common: • 1- tachycardia • 2- hypertension, • 3- mydriasis, • 4- dry and flushed skin, • 5- visual blurring, • 6- decreased GI motility (constipation), • 7- urinary retention, and delirium with hallucinations and convulsions.

12.  Abrupt withdrawal of a chronically administered cyclic antidepressant can cause a cholinergic rebound syndrome: • anorexia, nausea, vomiting, diarrhoea, sweating, myalgia, headache, fatigue, anxiety, insomnia, mania, akithisia or Parkinsonism

13. Drug Interactions • 1- Cyclic antidepressants potentiate the sedative effect of alcohol, and the hypertensive effect of sympathomimetics. • 2- They aggravate the anticholinergic effect of antiparkinsonian and antipsychotic drugs, and cause marked hyperpyrexia with convulsions and coma when combined with MAOIs. • 3- The effect of antihypertensive drugs is reduced.

14. 4- Serotonin reuptake inhibitors inhibit cytochrome P450-2D6 and can cause elevations in serum tricyclic antidepressant levels. • 5- While tricyclic antidepressants and MAOIs have been used concomitantly to treat severe depression, the combination has occasionally been associated with the development of serotonin syndrome. overdose with the combination of tricyclic antidepressants and MAOI appears to cause severe effects and has a high fatality rate.

15. Clinical (Toxic) Features •  Overdose results in seizures (especially common with maprotiline and amoxapine), which are generally brief in duration, tachycardia, hypotension, agitation, hallucinations, confusion including anticholinergic delirium, hyperthermia, ataxia, urinary retention, and coma. • Coma is usually short-lived, and most patients waken within 24 hours. •  Anticholinergic effects (mydriasis, tachycardia, urinary retention, decreased gastrointestinal motility) are common, but may be masked in severe overdose. •  Miosis may be present in deeply comatose patients. Nystagmus may occur.

16.  Rhabdomyolysis and renal failure may result from prolonged seizures or coma. •  Significant metabolic acidosis may develop in patients with prolonged seizures or hypotension. •  Neuroleptic malignant syndrome (NMS) has been reported. •  Respiratory depression is common with significant overdoses and may develop rapidly. Adult respiratory distress syndrome may occur after severe overdose.

17.  Cardiovascular toxicity results in myocardial depression, ventricular tachycardia, and fibrillation. Severe cardiac toxicity generally develops within six hours. • Myocardial infarction has been reported following overdose and with therapeutic use. •  The duration of coma with cyclic antidepressant overdose is generally less than 6 to 12 hours. • If this is prolonged beyond 24 hours, it indicates development of complications or concomitant ingestion of CNS depressants.

18.  Amitryptiline overdose may be associated with peripheral neuropathy, and extrapyramidal manifestations. •  Pulmonary oedema may present in 10 to 15% of patients with cyclic antidepressant overdose: diffuse bilateral pulmonary infiltrates and other features characteristic of ARDS. •  Uncommon manifestations include fulminant hepatic failure & bowel ischaemia, •  Pruritic erythematous rash, vesicular eruption, blistering and skin discolouration have also been reported. •  Withdrawal syndromes may occur after discontinuation of tricyclic antidepressants. • Symptoms associated with tricyclic antidepressant withdrawal may include nausea, diarrhoea, malaise, myalgias, headache, rhinorrhoea, anxiety, agitation, mania, insomnia, nightmares, arrhythmias and ventricular ectopy.

19. Treatment • 1. Patients with ECG changes should be monitored in the ICU until the mental status is baseline, the patient is asymptomatic, and the ECG has returned to normal for 24 hours. • 2. Supportive measures:  Maintain airway; intubate if indicated.  Monitor arterial blood gases.  Administer oxygen if necessary.  Treat hypotension with IV crystalloids, inotropes (dopamine), vasopressors (noradrenaline), etc., as necessary. • 3. Reduce drug absorption:  Stomach wash (within the first 6 hours).  Activated charcoal (1 gm/kg).

20. 4. Enhance drug elimination:  Multiple-dose activated charcoal.  Diuresis and haemodialysis are not effective. • 5. Treat convulsions: Diazepam 0.1 mg/kg IV • 6. Treat arrhythmias: •  Serum alkalinisation to a pH of 7.45 to 7.55 using intravenous boluses of sodium bicarbonate is recommended for patients with arrhythmias. •  Intubation and hyperventilation may be used as an adjunct to sodium bicarbonate to achieve serum alkalinisation, with careful monitoring of blood gases to avoid profound alkalaemia

21.  Conventional antiarrhythmics may also be necessary. Quinidine, disopyramide, and procainamide are contraindicated, as their effects on myocardial conduction are similar to that of the tricyclic antidepressants. •  Ventricular tachycardia—alkalinise (to 7.40 – 7.45 pH); lignocaine 1mg/kg IV, bolus, followed by infusion of 2 to 4 mg/min •  Bradycardia or heart block—alkalinise to 7.40 to 7.45 pH; isoprenaline; pacemaker. •  Flumazenil is contraindicated even if benzodiazepines are known coingestants; use of flumazenil in the setting of tricyclic antidepressant overdose has been associated with the onset of seizures and ventricular arrhythmias

22.  Selective Serotonin Reuptake Inhibitors (SSRI) These drugs constitute the second generation of antidepressant drugs and are much safer and better tolerated than the first generation drugs (cyclics and monoamine-oxidase inhibitors). • Important examples include citalopram, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, pizotifen, sertraline. • A related group of drugs comprises the selective serotonin-noradrenaline reuptake inhibitors (SNRIs), mainly represented by venlafaxine, milnacipram, and duloxetine. • For the sake of convenience, both groups are discussed together under one heading. Uses Treatment of depression, panic disorder, obsessive-compulsive disorder, sleep disorders, migraine & substance abuse.

23. Toxicokinetics  All SSRIs (except paroxetine) are rapidly absorbed on oral administration. Because of slower absorption in the case of paroxetine, symptoms of toxicity can be delayed. • Peak plasma concentrations are generally reached in about 2 to 8 hours depending on the drug. Sertraline is also slowly absorbed; peak plasma concentrations are reached approximately 5 to 8 hours after oral dosing. •  Protein binding ranges from 50% (for citalopam) to 99% (for sertraline). Fluoxetine binds to plasma proteins to the extent of 94%. •  The primary route of elimination of most of these drugs appears to be renal. Elimination half-lives range from 15 to 26 hours

24. Mode of Action  The SSRIs specifically inhibit the reuptake of serotonin, thereby potentiating the activity of neuronally released serotonin. •  Sertraline has a greater selectivity for inhibiting 5-HT uptake relative to noradrenaline than any other drug in this class of therapeutic agent. • Adverse Effects  Anorexia, dry mouth, nausea, vertigo, blurred vision, tremor, drowsiness, sexual dysfunction, seizures; suicidal ideation, mania, and paranoia; extrapyramidal effects; cardiac arrhythmias; hyponatraemia and syndrome of inappropriate antidiuretic hormone (SIADH) ; and serum sickness or flu-like symptoms.

25.  Serotonin syndrome: The serotonin syndrome is a disorder that can be caused by use of drugs or combinations of drugs which increase serotonin availability. • It most often occurs when two or more drugs which increase serotonin availability by different mechanisms are used simultaneously. • The SSRIs may cause the development of this syndrome when used alone, or (more commonly) when administered along with other serotonergic agents especially monoamine oxidase inhibitors

26. (MAOIs). - Main features include agitation, restlessness, confusion, disorientation, hallucinations, drowsiness or insomnia, tachypnoea, flushing, abdominal pain, ataxia, tremor, hypomania, myoclonus, muscle rigidity, hyperactivity, convulsions, sweating, salivation, tachycardia, mydriasis, nystagmus, teeth chattering, hyper- or hypotension, hyperpyrexia, coma and diarrhoea. • - Diagnostic criteria for serotonin syndrome include at least three of the following features: mental status changes (confusion, hypomania), agitation, myoclonus, hyperreflexia, sweating, shivering, tremor, diarrhoea, incoordination and fever. • - The syndrome usually occurs in the first 2 hours of the first dose of the drug and usually resolves within 6 to 24 hours of stoppage of the medication. • -

27. - Hyperthermia is characteristic of serotonin syndrome. • In severe cases core temperature may exceed 42°C. - Complications ensue including metabolic acidosis, lactic acidosis, rhabdomyolysis, myoglobinuria, renal and hepatic dysfunction. • - It is important to note that the serotonin syndrome has many similarities with neuroleptic malignant syndrome (NMS) However, NMS tends to have a slower onset and more prolonged duration of symptoms. Also, it is more frequently associated with fever and muscle rigidity than serotonin syndrome.

28. Treatment of serotonin syndrome: • - Benzodiazepines for agitation & convulsions. - Rapid external cooling. - Neuromuscular blockade (with non-depolarising paralytics) in severe cases. - Nitroprusside for severe hypertension; • - Noradrenaline, adrenaline, or phentolamine (NOT dopamine) for severe hypotension. - Benefit may be obtained in some cases with cyproheptadine, or propranolol. • Drug Interactions • - Diazepam: Concurrent administration of diazepam, with fluoxetine, may result in increased serum diazepam levels due to inhibition of diazepam metabolism by fluoxetine. • - MAO inhibitors: The combined use of fluoxetine (and other SSRIs) with MAO inhibitors may induce serotonin syndrome. - Tricyclics: Plasma levels of tricyclics may be greatly increased when coadministered with fluoxetine and other SSRIs.

29. - Clinical (Toxic) Features •  Acute SSRI overdose - abdominal pain, nausea, vomiting, diarrhoea, vertigo, lethargy, insomnia, diplopia, CNS depression, tremors, and rarely convulsions. • - ECG abnormalities (ventricular tachycardia). • - Hypotension has also been reported. • - Abrupt withdrawal of an SSRI after prolonged therapeutic use may cause vertigo, nausea, vomiting, fatigue, and myalgia. • A discontinuation syndrome of dizziness, lightheadedness, insomnia, fatigue, anxiety, agitation, nausea, headache, and sensory disturbances has been described after abrupt discontinuation of therapy with fluoxetine. • .

30. Treatment - supportive measures. • Syrup of ipecac is contraindicated, while stomach wash is usually not necessary. • - Monitor for evidence of serotonin syndrome. • - Admit those with significant clinical effects including seizures or persistent lethargy or arrhythmias. • - Sodium bicarbonate may be useful in treating QRS prolongation or arrhythmias. • - Because of the large volume of distribution and high degree of protein binding of SSRIs, haemodialysis, forced diuresis, haemoperfusion and exchange transfusion would not be expected to be useful in overdose

31.  Monoamine Oxidase Inhibitors (MAOIs) • Today MAOIs have been largely replaced by the cyclic antidepressants for the treatment of a variety of psychiatric disorders, but continue to be used in certain types of anxiety and phobias as well as treatment-resistant depression. • Examples of MAOIs include isocarboxacid, iproniazid, moclobemide, pargyline, phenelzine, pimozide, selegiline, toloxatone, and tranylcypromine. • - Irreversible MAOIs such as isocarboxacid, phenelzine, tranylcypromine, and selegiline are used in the treatment of Parkinsonism • - Monoamine oxidase inhibitors (MAOIs) are useful in the treatment of depression, anxiety disorders, panic disorders, obsessive-compulsive disorders, phobic disorders, narcolepsy and Parkinson’s disease. • Toxicokinetics - Monoamine oxidase inhibitors (MAOIs) are rapidly absorbed on oral administration and are metabolised by acetylation, followed by urinary excretion

32. Mode of Action - The MAOIs act (obviously) by inhibiting oxidative deamination and inactivation of monoamines of nervous system transmission, e.g. noradrenaline, dopamine, adrenaline, and serotonin. • As a result of MAO inhibition, the pool of noradrenaline in the presynaptic sympathetic nerve terminal is expanded which causes the elevation of CNS noradrenaline and dopamine. • - Meclobemide is selective MAO-A inhibitors. selegiline is selective MAO B inhibitors, while Phenelzine, tranylcypromine and isocarboxazid are non-selective MAOIs. Selectivity is lost in overdose.

33. Adverse Effects and Drug Interactions - Patients taking MAOIs are prone for multiple food interactions some of which are lifethreatening, ingestion of foods containing tyramine. • resulting in severe hypertensive crisis, tachycardia, severe occipital headache, hyperthermia, altered mental status, convulsions, and even intracranial haemorrhage and death. • - Combination of MAOIs with indirect acting sympathomimetic drugs can cause severe hypertension.

34. Drugs with the potential to cause this reaction include amphetamines, dopamine, cocaine, phentermine, ephedrine, - The MAOIs are also capable of causing the serotonin syndrome, especially when combined with SSRIs. • At least 14 days should elapse between the discontinuation of an MAOI and the initiation of SSRI therapy • - Addicts who abuse cocaine are at special risk of suffering a severe reaction when they are on MAOI medication. Features include severe headache, hyperthermia, tremor, convulsions, and death.

35. Clinical (Toxic) Features • 1. Overdose is characterised by an initial delay in presentation of upto 12 hours or more. • 2. Symptoms include anxiety, flushing, headache, nausea, tachycardia/bradycardia, hypertension/hypotension, agitation, delirium, hallucinations, nystagmus, tremors, muscle rigidity, convulsions, hyperthermia, profuse sweating, tachypnoea, respiratory depression, and cardiovascular collapse. 3. Pupils may be dilated and minimally reactive to light after MAOI overdose 4. Death occurs in some cases from complications such as ARDS and myoglobinuric renal failure.

36. 5. Overdose complicated by rhabdomyolysis or hypotension often leads to myoglobinuria, acute tubular necrosis and renal failure. • 6. Coagulopathy, haemolysis and thrombocytopenia may develop with MAOI overdose. • 8. Chronic use of these drugs (especially phenelzine and tranylcypromine) can lead to withdrawal reaction on abrupt cessation, characterised by anxiety, depression, confusion, hallucinations, nausea, vomiting, diarrhea and chills.

37. Treatment Due to the potential for delayed and severe toxicity, any patient with a history of acute MAOI overdose, even in the absence of symptoms in the first 4 to 6 hours, should be admitted for ICU monitoring and remain until stable for 24 hours. • The following measures are suggested for the treatment of adverse as well as toxic effects of MAOIs: • 1. Maintenance of airway, oxygen, assisted ventilation, etc.(as needed). • 2. Cardiac monitoring. • 3. Electrolytes should be monitored closely, particularly forhyperkalaemia. 4. Monitor liver and renal function, and CPK level. • 5. Severe hypertension should be treated with IV sodium nitroprusside or phentolamine. Methyldopa and guanethidine are contraindicated as they may potentiate hypertensive crises.

38. 6. Hypotension (or shock) can be managed by IV fluids, and vasopressors such as noradrenaline or dopamine, i.e. direct-acting alpha-adrenergic agonists. • 7. Ventricular tachyarrhythmias usually respond to lignocaine, phenytoin, or procainamide. • 8. If the patient is seen within a short time of overdosing, gut decontamination must be carried out, lavage, activated charcoal, cathartics. • 9. Foced acidic diuresis and haemodialysis are probably best avoided. • Clinical

39. 10. Muscle rigidity and agitation may respond to phenothiazines such as chlorpromazine. • Diazepam is however safer. In the presence of intractable muscle rigidity, neuromuscular paralysis with pancuronium may be necessary. • 11. Seizures are best treated with benzodiazepines. • 12. Hyperthermia can be managed with paracetamol and external cooling. • In severe cases (malignant hyperthermiatype), IV dantrolene is given at a dose of 2.5 mg/kg, every 6 hours, for 24 hours. As an alternative, bromocriptine can be administered. • .

40. 13. For rhabdomyolysis: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. • Diuretics such as mannitol or furosemide may be needed to maintain urine output. Urinary alkalinisation is not routinely recommended. • 14. Serotonin syndrome must be treated on the recommended lines outlined under SSRIs • 15. Patients should be placed on special diets low in tyramine-containing foods for at least 2 weeks post-exposure

41.  Atypical Antidepressants • 1- Bupropion - Bupropion is a unicyclic antidepressant which acts by selectively inhibiting neuronal reuptake of dopamine, noradrenaline, and serotonin. It also has moderate anticholinergic activity. • - Apart from its use as an antidepressant, bupropion is also said to be effective in the treatment of attention deficit disorder, reduction of cocaine use, and even in diminishing the craving for smoking. • - Owing to the riskof seizure induction, bupropion must never be combined with other drugs which can lower the seizure threshold. • - Bupropion is well-absorbed orally, with peak plasma levels within 2 hours. • - It is protein bound to the extent of 85%, has a volume of distribution of 19.8 to 47 L/kg, and a half-life ranging from 3.8 to 23 hours. • All of the dose is metabolized and 87% of the dose is excreted in the urine, as metabolites. • -

42. Overdose results in vertigo, vomiting, miosis, tachycardia, hypokalaemia, and convulsions. • In most cases, seizures are of short duration and may not require ongoing treatment. • - Massive overdose has resulted in cardiac arrest, severe hypoxia, and mixed respiratory and metabolic acidosis. • Auditory and visual hallucinations have been described frequently following bupropion overdose.

43. - Chronic use can cause rash, nocturia, ataxia, convulsions, dystonia, hallucinations, and hypomania. • Tremor is a common effect in higher therapeutic doses • - Treatment of overdose involves control of convulsions with IV diazepam. • Cardiac monitoring may be necessary. Monitor for seizures and mental status changes. Urine • myoglobin, serum creatinine and creatine kinase levels, etc., should be monitored for detecting rhabdomyolysis. • Hypokalaemia must be corrected. If the patient has been seen within a short time of the overdose, activated charcoal can be administered. Emesis and gastric lavage are known to aggravate convulsive tendency