Life threatening side effects of Psychotropics

Psychotropics life-threatening Side Effect

1. Seminar – other life threatening side effects of psychotropics By MD WASIM Under the guidance of DR GUNJAN SOLANKI

2. PSYCHOTROPIC MEDICATION THAT ACT ON THE CENTRAL NERVOUS SYSTEM MOOD BEHAVIOUR CONCIOUSNESS COGNITION PERCEPTION

3. TREAT THE SYMPTOMS OF MENTAL ILLNESS ANTIPSYCHOTICS MOOD STABILIZERS ANTIDEPRESSANTS ANXIOLYTICS/SEDATIVES/HYPNOTICS ANTI-DEMENTIA DRUGS

4. ANTIPSYCHOTIC RELATED LIFE THREATENING SIDE EFFECT QT PROLONGATION Antipsychotics block cardiac potassium channels are linked to prolongation of the cardiac QT interval, a risk factor for the ventricular arrhythmia torsade de pointes,which is often fatal. Overall risk is probably dose‐related ,usually plasma level-dependent. The cardiac QT interval (usually cited as QTc – QT corrected for heart rate) is a useful,but imprecise indicator of risk of torsade de pointes and of increased cardiac mortality .

5. The QT interval is the time from the start of the Q wave to the end of the T wave. It represents the time taken for ventricular depolarisation and repolarisation. The QT interval is inversely proportional to heart rate. The QT lengthens at slower heart rates. An abnormally prolonged QT is associated with an increased risk of ventricular arrhythmias, especially  Torsades de Pointes.

6. HOW TO MEASURE QT INTERVAL The QT interval should be measured in either lead II or V5-6 Several successive beats should be measured, with the maximum interval taken Large U waves (> 1mm) that are fused to the T wave should be included in the measurement Smaller U waves and those that are separate from the T wave should be excluded The  maximum slope intercept method  is used to define the end of the T wave (see below)

7. Corrected QT The corrected QT interval ( QTc ) estimates the QT interval at a heart rate of 60 bpm . This allows comparison of QT values over time at different heart rates and improves detection of patients at increased risk of arrhythmias. Bazett’s formula:  QT C  = QT / √ RR The RR interval is given in seconds (RR interval = 60 / heart rate). Causes of a prolonged QTc-Hypokalemia,Hypomagnesemia,Hypocalcaemia,Hypothermia,MI,Post cardiac arrest,Raised ICT,Congenital long QT syndrome,Drugs .

8. The QT interval broadly reflects the duration of cardiac repolarisation. Lengthening of repolarisation duration induces heterogeneity of electrical phasing in different ventricular structures (dispersion), which in turn allows the emergence of early after depolarisations (EADs) which may provoke ventricular extrasystole and torsade de pointes. normal limits (440 msec for men; 470 msec for women). QTc values over 500 msec to a clearly increased risk of arrhythmia. QTc determination remains an important measure in estimating risk of arrhythmia and sudden death.

9. Other ECG changes Other reported antipsychotic‐induced changes include atrial fibrillation, giant P waves, T‐wave changes and heart block. Effect of antipsychotics on QTc High‐effect drugs = extensive average QTc prolongation usually >20 msec at normal clinical doses. Eg . any iv antipsychotic, Pimozide , Sertindole,Any drug or combination of drugs used in doses exceeding recommended maximum... Moderate‐effect drugs = prolong QTc by >10 msec on average at normal clinical doses or where ECG monitoring is officially recommended in some circumstances. Eg . amisulpride,CPZ,halopeidol,quetiapine,ziprasidone ... Low‐effect drugs = severe QTc prolongation has been reported only following overdose or small average increases <10 msec at clinical doses. Eg.asenapine,clozapine,flupenthixol,olanzapine,resperidone,sulpride.

10. DIABETIC KETOACIDOSIS The mechanisms involved in the development of antipsychotic‐related diabetes areunclear , but may include 5HT2A/5HT2C antagonism, increased plasma lipids, weight gain and leptin resistance.Insulin resistance may occur in the absence of weight gain. Degree of risk Antipsychotic drug High risk= Clozapine , olanzapine (insulin resistance,death reported d/t diabetic ketoacidosis ) Moderate risk= Quetiapine , risperidone , phenothiazines Low risk=High potency FGAs (e.g. haloperidol) Minimal risk= Aripiprazole , amisulpride , asenapine , lurasidone , ziprasidone

11. DKA usually develops slowly. But when vomiting occurs, this life-threatening condition can develop in a few hours. Early symptoms include the following: Thirst or a very dry mouth Frequent urination High blood glucose (blood sugar) levels High levels of ketones in the urine Then, other symptoms appear: Constantly feeling tired Dry or flushed skin Nausea, vomiting, or abdominal pain (Vomiting can be caused by many illnesses, not just ketoacidosis . If vomiting continues for more than 2 hours, contact your health care provider.) Difficulty breathing Fruity odor on breath A hard time paying attention, or confusion

12. Managing diabetic ketoacidosis (DKA) in an intensive care unit during the first 24-48 hours always is advisable. When treating patients with DKA, the following points must be considered and closely monitored: Correction of fluid loss with intravenous fluids Correction of hyperglycemia with insulin Correction of electrolyte disturbances, particularly potassium loss Correction of acid-base balance Treatment of concurrent infection, if present It is essential to maintain extreme vigilance for any concomitant process, such as infection, cerebrovascular accident, myocardial infarction, sepsis, or deep venous thrombosi .

13. DRUG INDUCED SIADH kidney retains an excessive quantity of solute‐free water. Serum osmolality is low and urine osmolality relatively high. The prevalence of SIADH has been estimated to be as high as 11% in acutely ill psychiatric patients. Hyponatraemia presents as confusion, nausea, headache and lethargy.As the plasma sodium falls, these symptoms become increasingly severe and seizures and coma can develop. phenothiazines , haloperidol, pimozide,risperidone , quetiapine , olanzapine , aripiprazole and clozapine . Overall prevalence of antipsychotic‐induced hyponatraemia has been estimated at 0.004%-26.1% of patients. Desmopressin use (for clozapine ‐induced enuresis) can also result in hyponatraemia . Severe hyperlipidaemia and/or hyperglycaemia lead to secondary increases in plasma volume and ‘ pseudohyponatraemia ’. Both are more common in people treated with antipsychotic drugs than in the general population and should be excluded as Causes.

14. MANAGMENT If mild, fluid restriction with careful monitoring of serum sodium. Refer to specialist medical care if Na < 125 mmol /L Switching to a different antipsychotic drug. There are insufficient data available to guide choice. Be aware that cross‐sensitivity may occur (the individual may be predisposed and the choice of drug relatively less important) Consider demeclocycline . Lithium may be effective but is a potentially toxic drug. Remember that hyponatraemia predisposes to lithium toxicity

15. PNEUMONIA The mechanism by which antipsychotics increase the risk of pneumonia is not known.Possibilities include sedation (risk seems to be highest with drugs that show greatest H1 antagonism); dystonia or dyskinesia ; dry mouth causing poor bolus transport and so increasing the risk of aspiration; general poor physical health;or perhaps some illdefined effect on immune response.With clozapine , pneumonia may also be secondary to constipation. More recently, a study of patients with bipolar affective disorder found that clozapine , olanzapine and haloperidol were linked to increased rates of pneumonia while lithium was protective .

16. Clozapine : serious haematological and cardiovascular adverse effects Agranulocytosis - Clozapine can cause serious life‐threatening adverse effects, of which agranulocytosis (0.8%) is the best known. The mechanism of clozapine -induced agranulocytosis is not clear. The target cells affected are the myeloid precursors & mature neutrophil . There is no convincing evidence of direct toxicity of the parent compound or its stable metabolites ( demethyl-clozapine and clozapine N-oxide). Clozapine is also metabolised by liver microsomes , peripheral blood neutrophils and their bone marrow precursors to a chemically reactive intermediate that has been postulated to be a nitrenium ion. This toxic metabolite has been shown to covalently bind to neutrophil proteins, suggesting that it may be involved in the pathogenesis of the toxicity .

17. The nitrenium ion may bind to essential cellular proteins and disrupt neutrophil function or, alternatively, it may act as a hapten and initiate an immune reaction resulting in immune-mediated destruction of the neutrophil . Indirect evidence exists to support both mechanisms, although clear direct evidence is still lacking. The role of cytokines and apoptosis in the pathogenesis of the agranulocytosis is unclear.The reason why only approximately 1% of individuals who are treated with clozapine are affected by agranulocytosis has not been elucidated .

18. Thromboembolism The risk of thromboembolism was estimated to be 1 in 2000 to 1 in 6000 patients treated. Thromboembolism may be related to clozapine’s observed effects on antiphospholipid antibodies and platelet aggregation.It seems most likely to occur in the first 3 months of treatment but can occur at any time. Other antipsychotics are also strongly linked to thromboembolism although clozapine appears to have the most reports. Risk of fatal pulmonary embolism is estimated to be around 1 in 4500 patients treated.

19. Myocarditis and cardiomyopathy Myocarditis seems to occur within 6–8 weeks of starting clozapine (median 3 weeks); cardiomyopathy may occur later in treatment (median 9 months) but both may occur at any time. patients should be closely monitored for signs of myocarditis especially in the first few months of treatment.Symptoms include hypotension, tachycardia, fever, flu‐like symptoms, fatigue, dyspnoea (with increased respiratory rate) and chest pain.Signs include ECG changes (ST depression),enlarged heart on radiography/echo and eosinophilia .

20. rapid dose increases, concurrent use of sodium valproate , and older age (31% increased risk for each additional decade) are the risk factor. Cardiomyopathy should be suspected in any patient showing signs of heart failure,which should provoke immediate cessation of clozapine and referral. Presentation of cardiomyopathy varies somewhat so any reported symptoms of palpitations, chest pain, syncope, sweating, decreased exercise capacity or breathing difficulties should be closely investigated. Risk of fatal myocarditis or cardiomyopathy may be as high as 1 in 1000 patients. Younger patients may have an increased risk of sudden death.

21. MOOD STABILIZERS RELATED LIFE THREATENING SIDE EFFECT LITHIUM induced renal reaction In the majority of patients, lithium impairs renal concentrating ability, The concentrating defect is not always reversible after lithium discontinuation, suggesting that both functional and structural changes have occurred in the distal tubules and collecting ducts. Polyuria is the most troublesome renal effect of lithium. A 24-hour urine volume of more than 3 L (1 to 2 L is normal) has been reported in as many as 35 percent of patients taking lithium.

22. Lithium increases urine volume: primarily by inhibiting the effect of antidiuretic hormone. disruption of the aquaporin-2 shuttle and CNS mechanisms. Severe polyuria can be socially and occupationally compromising; a cause of insomnia, weight gain (through consumption of high-calorie beverages), poor nutrition, and noncompliance; and potentially dangerous if dehydration occurs. Treatment considerations include (1) adequate fluid replacement, (2) using the lowest effective dosage, (3) and counteractive medications such as thiazides or potassium sparing diuretics, or indomethacin ( Indocin ).

23. Lithium can alter kidney morphology: nonspecific interstitial fibrosis(most common). associated with renal insufficiency. There have been well-documented reports of lithium-related nephrotic syndrome and of incomplete distal renal tubular acidosis. Regular monitoring of renal function is an essential part of long-term lithium therapy. Precaution- Decreases in body fluid (perspiration) can lead to lithium intoxication. Excessive sodium intake lowers lithium concentrations.

24. LITHIUM TOXICITY Mild to moderate intoxication(Li-1.5 to 2.0 meq /l) G.I.- Vomiting. Dryness of mouth. Abdominal pain. NEUROLOGIC- Ataxia, dizziness and slurred speech. Nystagmus , lethargy &muscle weakness. Moderate to severe intoxication(Li-2.0 to 2.5 meq /l) G.I.- Anorexia and Persistent nausea and vomiting. NEUROLOGIC- Blurred vision. Muscle fasciculations . Clonic limb movements. Hyperactive DTR. Dilirium . Convulsion. Syncope, stupor and coma. 25

25. SEVERE INTOXICATION(Li-more than 2.5 meq /l) Generalized convulsion. Oliguria . Renal failure and death MANAGEMENT OF LITHIUM TOXICITY Shift patient to emergency room. Discontinue lithium and ask ingest to fluid, if possible. Do complete physical examination with MSE. Lithium level, serum electrolyte, RFT and ECG should be done as soon as possible. For significant acute ingestion, do gastric lavage and absorption with activated charcoal

26. Vigorous hydration and maintenance of electrolyte is essential. Any patient with lithium greater than 4.0 meql /l, hemodialysis should be initiated. Repeat dialysis until sign and symptom disappear. Maternal lithium concentration must be monitored after pregnancy, because of the significant decrease in renal lithium excretion. Adequate hydration can reduce risk toxicity during labor. Signs of lithium toxicity in infants include lethargy, cyanosis, abnormal reflexes, and sometime hepatomegaly . Lithium should be used with caution in diabetic persons, to avoid diabetic ketoacidosis .

27. SODIUM VALPROATE Rare serious side effects—as noted in the FDA black box warnings—include: hepatic failure, Liver failure and death from liver failure has occurred in patients taking valproate . This has usually occurred within the first 6 months of treatment. Symptoms of liver problems ( eg , a general feeling of discomfort, sluggishness, unusual tiredness or weakness, swelling of the face, loss of appetite, vomiting, stomach pain, dark urine, pale stools, or yellowing of the skin or eyes). In patients who have seizures, loss of seizure control may occur. You should have lab tests done before and during treatment to check for liver problems.

28. pancreatitis , drug induced pancreatitis is rare entity,its 0.1-2% of all acute pancreatitis cases. Symptoms of acute pancreatitis : Upper abdominal pain that radiates into the back; it may be aggravated by eating, especially foods high in fat. Swollen and tender abdomen Nausea and vomiting Fever Increased heart rate.

29. hyperammonemic encephalopathy in patients with urea cycle disorders. Valproate -induced hyperammonemic encephalopathy (VHE) is an unusual complication characterized by a decreasing level of consciousness, focal neurological deficits, cognitive slowing, vomiting, drowsiness, and lethargy . It is important to obtain baseline hepatic function tests before valproate treatment. Close clinical observation.

30. OTHERS valproate was associated with an increase in pulmonary adenomas and fibrosarcomas . There is no evidence to suggest a carcinogenic effect in humans.

31. CARBAMAZEPINE 3% of patients treated with carbamazepine develop a generalised erythematous rash. Serious exfoliative dermatological reactions can rarely occur ( steven johanson syndrome); vulnerability is genetically determined. SJS= Stevens–Johnson syndrome , a form of toxic epidermal necrolysis , is a life-threatening skin condition, in which cell death causes the epidermis to separate from the dermis. The syndrome is thought to be a hypersensitivity complex that affects the skin and the  mucous membranes . 

32. Begins with fever, sore throat, and fatigue, which is commonly misdiagnosed and therefore treated with antibiotics. Ulcers and other lesions begin to appear in the mucous membranes, almost always in the mouth and lips, but also in the genital and anal regions. Those in the mouth are usually extremely painful and reduce the patient's ability to eat or drink. Conjunctivitis of the eyes occurs in about 30% of children who develop SJS. A rash of round lesions about an inch across arises on the face, trunk, arms and legs, and soles of the feet, but usually not the scalp. SJS constitutes a dermatological emergency

33. PROGNOSIS- SJS (with less than 10% of body surface area involved) has a mortality rate of around 5%. The mortality for toxic epidermal necrolysis (TEN) is 30–40%. 

34. ANTIDEPRESSANT RELATED LIFE THREATENING SIDE EFFECT Tricyclic antidepressants have established arrhythmogenic activity which arises as a result of potent blockade of cardiac sodium channels and variable activity at potassium channels.ECG changes produced include PR, QRS and QT prolongation and the Brugada syndrome. ECG monitoring is a more meaningful and useful measure of toxicity than plasma level monitoring. antidepressants are associated with arrhythmia (ranging from clinically insignificant to life threatening) and sudden cardiac death.

35. The Fatal Toxicity Index (FTI) is a measure of the number of overdose deaths per million (FP10) prescriptions issued. FTI figures suggest high toxicity for tricyclic drugs (especially dosulepin but not lofepramine ), medium toxicity for venlafaxine and moclobemide , and low toxicity for SSRIs, mirtazapine and reboxetine .

36. Antidepressant‐induced hyponatraemia Most antidepressants have been associated with hyponatraemia ; the onset is usually within 30 days (median 11 days) of starting treatment and is probably not doserelated.The most likely mechanism of this adverse effect is the SIADH SSRIs are more likely to cause hyponatraemia than TCAs or mirtazapine , and that older women who are co‐prescribed other medication known to reduce plasma sodium are at greatest risk. All patients taking antidepressants should be observed for signs of hyponatraemia (dizziness, nausea, lethargy, confusion, cramps, seizures).

37. BLEEDING Normally Serotonin is released from platelets in response to vascular injury and promotes vasoconstriction and morphological changes in platelets that lead to aggregation. SSRIs inhibit the SERT, responsible for the uptake of serotonin into platelets. SSRIs will deplete platelet serotonin. Reduced ability to form clots and a subsequent increase in the risk of bleeding.

38. The excess risk of bleeding is not confined to upper GI bleeds. The risk of lower GI bleeds may also be increased and an increased risk of uterine bleeding has also been reported.SSRIs should be used cautiously in patients with cirrhosis or other risk factors for internal bleeding. Co‐prescription of low‐dose aspirin at least doubles the risk of GI bleeding associated with SSRIs alone and co‐prescription of NSAIDs approximately quadruples risk. Use of SSRIs in the perioperative period has been associated with a 20% increase in inpatient mortality (absolute risk 1:1000)

39. SSRIs increase the risk of GI, cerebral and perioperative bleeding (those undergoing orthopaedic or breast surgery may be at greatest risk). Risk is increased still further in those also receiving aspirin, NSAIDs or oral anticoagulants. Try to avoid SSRIs in patients receiving NSAIDs, aspirin or oral anticoagulants or with history of cerebral or GI bleeds. If SSRI use cannot be avoided, monitor closely and prescribe gastroprotective proton pump inhibitors.

40. ANTIANXIETY/SEDATIVE/HYPNOTICS RELATED LIFE THREATENING SIDE EFFECT Dose Dependent Action 41

41. BZDS TOXICITY Benzodiazepines generally are thought to be safe and death is rare. Mortality and morbidity from a pure oral BZD overdose is rare; it usually occurs in conjunction with concomitant alcohol ingestion or use of other sedative-hypnotics. Intravenous administration or overdose of ultrashort -acting BZDs ( eg , triazolam ) is more likely to result in apnea and death. Elderly individuals and very young persons are more susceptible to the CNS depressant effects of BZDs than people in other age groups. Intravenous administration is associated with greater degrees of hypotension than other routes of administration and occasional cardiac and respiratory arrest.

42. Signs and symptoms Dizziness,Confusion,Drowsiness,Unresponsiveness , Anxiety, and Agitation. Blurred vision and Nystagmus . Slurred speech, ataxia, Weakness. Hypotension. Respiratory depression. Coma.

43. Management Flumazenil is a competitive BZD receptor antagonist and should be used cautiously because it has potential to precipitate BZD withdrawal in chronic users, resulting in seizures. Flumazenil administration is contraindicated in mixed overdoses ( eg , TCAs) because BZD reversal can precipitate seizures and cardiac arrhythmias.

44. BZDS WITHDRAWAL Withdrawal is likely to occur after abrupt cessation of benzodiazepines or a significant sudden decrease in the absolute dosage among dependent patients Withdrawl symptoms: agitation, anxiety, dysphoria , Increased awareness of sensory stimuli, Perceptual disturbances, depersonalization, Confusion, delirium, and seizures appreciable increase of arterial pressure and myocardial ischemia may occur as a result of abrupt cessation.

45. BARBITURATES TOXICITY(PHENOBARBITONE) Strong physiological dependence may develop upon long-term use. Depression of the medullary respiratory centers is the usual cause of death of sedative/hypnotic overdose. Also loss of brainstem vasomotor control and myocardial depression. Withdrawal is characterized by increase anxiety, insomnia, CNS excitability and convulsions. No medication against overdose with BARBs.

46. In severe intoxication, the patient is comatose; respiration is affected early. Breathing may be either slow or rapid and shallow. Eventually, blood pressure falls because the effect of the drug and of hypoxia on medullary vasomotor centers ; depression of cardiac contractility and sympathetic ganglia also contributes. Pulmonary complications ( e.g., atelectasis , edema , and bronchopneumonia) and renal failure are likely to be the fatal complications of severe barbiturate poisoning. MANAGMENT The treatment of acute barbiturate intoxication is based on general supportive measures. Hemodialysis or hemoperfusion is necessary only rarely, and the use of CNS stimulants is contraindicated because they increase the mortality rate.

47. ANTI DEMENTIA DRUGS RELATED AChE -Is may have vagotonic effects on heart rate (i.e. bradycardia ). The potential for this action may be of particular importance in patients with ‘sick sinus syndrome’ or other supraventricular cardiac conduction disturbances, such as sinoatrial or atrioventricular block. Potential cardiac adverse effects associated with AChE -Is were raised following findings from controlled trials of galantamine in mild cognitive impairment (MCI) in which increased mortality was associated with galantamine compared with placebo (1.5% versus 0.5% respectively). Although no specific cause of death was predominant, half the deaths reported were due to cardiovascular disorders. As a result, the FDA issued a warning restricting galantamine in patients with MCI. The relevance in Alzheimer’s disease remains unclear.

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