Lithium

1.   Lithium

2. PERSPECTIVE • Lithium has been used as a medicinal agent since the mid-1800s, when lithium salts were popularized as a treatment for gout (lithium carbonate and lithium citrate), a sedative for manic patients (lithium bromide), and as a treatment for epilepsy (lithium bromide). In 1929, the soft drink “7 Up,” whose original name was “Bib-Label Lithiated Lemon-Lime Soda,” included lithium citrate as an ingredient (until 1950) and was marketed as a patent medicine to cure hangovers.

3. Despite the introduction of newer and safer medications, lithium is established as the most effective long-term treatment to prevent recurrences of mania and bipolar disorder. Lithium treatment also appears to substantially decrease the risk of suicide and suicide attempts.

4. PRINCIPLES OF DISEASE • The precise mechanism of action of lithium as a mood-stabilizing agent is not fully understood. Lithium increases serotonin release and serotonin receptor sensitivity, and it also inhibits norepinephrine and dopamine release from nerve terminals.

5. Immediate-release lithium is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations occur 0.5 to 3 hours after a single oral dose, with complete absorption within 8 hours. Sustained-release lithium preparations exhibit variable absorption, with a delayed peak of 6 to 12 hours.

6. Lithium renal elimination is increased by factors that decrease glomerular filtration rate (e.g., dehydration) or sodium concentration (e.g., hyponatremia). Medications such as nonsteroidal anti-inflammatory drugs, diuretics, and angiotensin-converting enzyme inhibitors may increase lithium levels by interfering with renal lithium elimination.

7. CLINICAL FEATURES • Clinical manifestations of lithium poisoning can be classified based on whether the poisoning is due to acute toxicity, chronic toxicity, or acute-on-chronic toxicity. • Acute toxicity represents an overdose of lithium in a patient without any lithium body stores. Gastrointestinal symptoms such as nausea, vomiting, and diarrhea are the earliest and most common presentation of toxicity.

8. Lithium also causes electrocardiographic effects, including bradycardia, T wave flattening or inversion, and QT prolongation. • Fortunately, significant cardiac dysrhythmias following lithium poisoning are rare. • Neurotoxicity is delayed because of the time required for lithium to distribute to the brain.

9. In chronic toxicity, the patient, who takes lithium regularly and has significant lithium body stores, develops toxicity because of increased absorption or decreased lithium renal elimination (e.g., dehydration, drug interactions, and renal insufficiency). • Neurotoxicity is the predominant presentation. • Mild toxicity may manifest as a worsening tremor.

10. Progressively more severe signs of neurotoxicity include drowsiness, hyper-reflexia, confusion, clonus, coma, seizures, and extrapyramidal signs. The syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) has been described and is defined as persistent neurologic dysfunction attributed to lithium toxicity persisting 2 months after lithium cessation. Typical SILENT presentations include cerebellar dysfunction, persistent extrapyramidal syndromes, brainstem dysfunction, and dementia. The presence of fever is also considered a poor prognostic sign and possible precipitant of SILENT

11. Finally, in acute-on-chronic toxicity, a patient who is already taking lithium ingests an additional quantity of lithium in excess of the prescribed dosage. The clinical presentation is signs and symptoms of both acute and chronic toxicity, including gastrointestinal and neurologic symptoms.

12. Lithium use is also considered a risk factor for neuroleptic malignant syndrome.

13. DIAGNOSTIC STRATEGIES • Since the signs and symptoms of lithium toxicity are nonspecific and are often delayed following acute overdose, a serum lithium level should be obtained in any patient suspected of acute or chronic lithium poisoning. Obtaining serum electrolytes may be helpful in patient management. Increased serum sodium may indicate lithium-induced nephrogenic diabetes insipidus, whereas the serum creatinine level may help determine whether extracorporeal removal is required.

14. Thyroid functions should also be obtained if clinical thyroid disease is suspected. Finally, obtaining an electrocardiogram and a serum acetaminophen level should be considered for acute, intentional ingestions to evaluate for the presence of co-ingestants.

15. MANAGEMENT • There is no antidote for lithium poisoning; consequently, the management of lithium toxicity includes selected gastrointestinal decontamination (for acute overdose only), techniques to increase the elimination of lithium (renal and extracorporeal) from the body, and supportive care.

16. Gastrointestinal Decontamination • Both oral activated charcoal and gastric lavage are ineffective in the management of lithium poisoning. Lithium is poorly adsorbed by activated charcoal. Gastric lavage is ineffective for several reasons. The immediate-release lithium preparations are usually absorbed from the gastrointestinal tract too quickly for lavage or whole bowel irrigation to be effective.

17. In addition, lithium-induced emesis would be expected to occur very quickly following an ingestion of immediate-release lithium, thereby limiting its own gastrointestinal absorption and making any attempt at gastric lavage potentially hazardous. Finally, sustained-release lithium tablets are too large to fit through an orogastric tube.

18. Whole-bowel irrigation with polyethylene glycol is the recommended gastrointestinal decontamination treatment for any overdose of sustained-release lithium preparation.

19. Techniques to Increase Elimination • Lithium can be removed by increasing renal elimination as well as by extracorporeal methods. • Fluid resuscitation with sodium chloride (normal saline) to correct hyponatremia and dehydration is the recommended method to maximize renal lithium elimination. Unless there are contraindications to aggressive volume expansion (e.g., renal insufficiency, congestive heart failure), administration of intravenous normal saline at a twice maintenance rate is recommended.

20. The most effective technique to eliminate lithium from the body is hemodialysis. Endogenous lithium renal clearance is approximately 15 to 20 mL/min, whereas hemodialysis lithium clearance is approximately 100 mL/min.

21. Hemodialysis is primarily used for clinical deterioration (e.g., seizures and decreased level of consciousness), inadequate endogenous lithium clearance (e.g., renal insufficiency), or inability to enhance renal elimination through volume expansion (e.g., congestive heart failure, cirrhosis, pancreatitis, and sepsis). Although it may not correlate directly with toxicity, hemodialysis is recommended for a serum lithium level greater than 4.0 mEq/L for acute toxicity and greater than 2.5 mEq/L for chronic toxicity.

22. DISPOSITION • Hospital admission should be considered for any patient with suspected lithium poisoning with abnormal neurologic signs (e.g., hyper-reflexia, clonus, altered sensorium, or seizure) or any asymptomatic patient after acute overdose with increasing lithium levels. In addition, hospitalization at a center with emergency dialysis capability is preferable.

24.  Antipsychotics

25. Antipsychotics PERSPECTIVE • used to treat agitation and psychosis caused by schizophrenia, mania, acute idiopathic psychosis, alcohol withdrawal hallucinosis, and Alzheimer's disease. • are often divided into three broad categories based on their receptor profiles, clinical effects, and adverse effects • All antipsychotic medications effectively treat the positive symptoms of psychotic disorders; they reduce hallucinations, control agitation, and aid in restructuring disordered thinking.

26. Antipsychotics ANATOMY AND PHYSIOLOGY • block dopamine receptors • All antipsychotic agents reduce the positive symptoms of schizophrenia by blocking the dopamine D2 receptor subtype in the mesolimbic region of the brain. • Blockade of D2 receptors in the nigrostriatal brain region produces undesired extrapyramidal movement disorders.

27. Antipsychotics ANATOMY AND PHYSIOLOGY • Blockade of D2 receptors in the mesocortical brain region impairs cognition and worsens the negative symptoms of schizophrenia. • Atypical antipsychotic agents block both D2 and serotonin 5-HT2A receptors. • These agents have lower affinity for dopamine receptor antagonism and more selective binding of D2 receptors in the mesolimbic versus nigrostriatal areas of the brain, resulting in a lower frequency of EPS and TD.

28. Antipsychotics ANATOMY AND PHYSIOLOGY • The serotonin receptor antagonism is thought to reduce EPS effects and improve the negative symptoms of schizophrenia. • Some atypical antipsychotics have serotonin 5-HT1A receptor agonism, a functionally opposite effect of 5-HT2A receptor antagonism, producing clinical effect in combination with D2 receptor antagonism.

29. Antipsychotics ANATOMY AND PHYSIOLOGY • Some antipsychotic medications have additional clinical uses. • The antiemetic effects of prochlorperazine, promethazine, and droperidol result from blockade of dopamine receptors in the chemoreceptor trigger zone of the medulla. • Hydroxyzine controls itching by blocking histamine (H1) receptors.

30. Antipsychotics ANATOMY AND PHYSIOLOGY • Prochlorperazine and droperidol abort migraine headaches by preventing dopamine-mediated meningeal artery vasodilation. • Chlorpromazine can treat severe hiccups. Haloperidol is the drug of choice for certain nonpsychiatric diseases characterized by movement disorders, including Tourette's syndrome and Huntington's chorea.

31. PATHOPHYSIOLOGY • Extrapyramidal syndromes can be divided into two groups based on the time of onset after initiating drug therapy. • The acute EPSs include dystonia, akathisia, and parkinsonism. • These adverse effects are caused by blockade of nigrostriatal D2 receptors and reduced by blocking muscarinic receptors. • The propensity for antipsychotics to produce EPSs is inversely related to the agents’ muscarinic receptor antagonism.

32. PATHOPHYSIOLOGY • The delayed-onset syndromes, including TD and tardive dystonia, develop after prolonged use of antipsychotic medications thought to occur from chronic dopamine receptor blockade in the nigrostriatal area leading to D2 receptor upregulation and hypersensitivity to dopamine. • The pathophysiology of NMS, an idiosyncratic reaction to antipsychotic medication, is unknown,

33. PATHOPHYSIOLOGY • Most antipsychotic medications produce cardiovascular side effects. • The most common side effect is orthostatic hypotension with reflexive tachycardia due to alpha-adrenergic blockade. • Many agents cause conduction delays, predominantly QT prolongation. • Blockade of the delayed inward rectifier potassium current prolongs repolarization during the cardiac action potential and potentially causes torsades de pointes (TDP).

34. PATHOPHYSIOLOGY • The phenothiazines, particularly thioridazine and mesoridazine, have the greatest risk of cardiac toxicity. • QT prolongation has also been reported with the butyrophenones, haloperidol and droperidol. • The atypical antipsychotics produce less cardiotoxicity than the traditional agents

35. PATHOPHYSIOLOGY • Seizure rarely occurs with antipsychotic drugs, but clozapine has the highest seizure incidence. • Some atypical antipsychotics have been associated with diabetes and dyslipidemia, especially clozapine and olanzapine, but the cause has not been established.

36. CLINICAL FEATURES Acute Overdose • In overdose, antipsychotic medications produce signs and symptoms that are exaggerations of the clinical effects. • Most patients will develop symptoms within a few hours. • CNS depression is universally present, ranging from mild sedation and confusion to coma and loss of brainstem reflexes. • Airway reflexes can be impaired.

37. CLINICAL FEATURES Acute Overdose • Respiratory depression can occur after a massive overdose with profound CNS depression. • Mild orthostatic hypotension is a common finding from alpha-adrenergic blockade. • EPS has been reported with the traditional and atypical antipsychotics.

38. CLINICAL FEATURES Acute Overdose • Extremity twitching is common. With the exception of clozapine, seizures rarely occur in overdose.

39. Acute Extrapyramidal Syndromes • Acute dystoniamanifests as involuntary motor tics or spasms that most often involve the facial, neck, back, or limb muscles. • Dystonic reactions usually develop within the first several doses of treatment or after a large increase in dosage. • Oculogyric crisis, characterized by continuous rotatory eye movements, has also been reported.

40. Acute Extrapyramidal Syndromes • Laryngeal dystoniais a rare but life-threatening form of dystonia that manifests as stridor, difficulty breathing, or a choking sensation.

41. Acute Extrapyramidal Syndromes • Akathisia, a subjective feeling of restlessness associated with objective motor restlessness, is often mistaken for worsening agitation, leading incorrectly to an increase in antipsychotic dose. • Akathisia usually develops within the first few days of treatment, but 40% of patients given 10 mg of intravenous (IV) prochlorperazine developed akathisia within 1 hour.

42. Acute Extrapyramidal Syndromes • parkinsonian syndrome of bradykinesia, masked facies, shuffling gait, muscular rigidity, and resting tremor frequently develops during the first weeks of therapy with low-potency and high-potency neuroleptic-antipsychotic agents. • Perioral tremor(rabbit syndrome), in which the lip and nose movements resemble those of a rabbit, can also develop after prolonged therapy.

43. Tardive Dyskinesia • TD is a chronic movement disorder induced by prolonged use of antipsychotic medication. • Typical signs of TD include quick, involuntary movements of the face (blinking, grimaces, tongue movements, and chewing), extremities, or trunk. • Twenty percent of patients treated with long-term traditional antipsychotics are affected.

44. Tardive Dyskinesia • The risk of development is much lower with the atypical agents. • TD is difficult to treat and frequently permanent. • Reducing the antipsychotic dose or changing to an atypical agent should be considered. • TD improves in many patients switched to clozapine

45. Tardive Dyskinesia • Respiratory dyskinesia, a variant of TD, is characterized by orofacial dyskinesia, dyspnea, dysphonia, and respiratory alkalosis. • This chronic disorder often goes undiagnosed and can cause repeated bouts of aspiration pneumonia.

46. Neuroleptic Malignant Syndrome • NMS is a serious idiosyncratic drug reaction that typically develops during the first month of therapy but has occurred during stable drug regimens. • Risk factors include rapid drug loading, high dosage, high-potency antipsychotics, parental formulations, dehydration, preceding psychomotor agitation, and previous episodes of NMS.

47. Neuroleptic Malignant Syndrome Other medications may contribute to NMS, including • lithium, which inhibits dopamine secretion • withdrawal from dopaminergic agents used to treat Parkinson's disease. • The incidence 0.02% The atypical antipsychotic agents, including clozapine, risperidone, olanzapine, quetiapine, and aripiprazole, have been associated with NMS.

48. Diagnostic Criteria and Clinical Features of Neuroleptic Malignant Syndrome

49. Neuroleptic Malignant Syndrome • Other features of NMS may include sialorrhea, dysarthria, dysphagia, metabolic acidosis, liver function elevations, sodium imbalance, dehydration, elevations in serum catecholamines, coagulopathy, generalized slowing on the electroencephalogram (EEG), pulmonary embolism, and renal failure. • Atypical presentations may lack full diagnostic criteria for NMS.

50. Neuroleptic Malignant Syndrome • Most patients develop the cardinal features of altered mental status, muscle rigidity, hyperthermia, and autonomic nervous system instability over several hours to days.