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: QTC = 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

12. 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

13. 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.

14. 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.

15. 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

16. 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.

17. 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.

18. • 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.

19. 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.

20. 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.

21. • 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.

22. 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.

23. • Lithium increases urine volume:
o primarily by inhibiting the effect of antidiuretic hormone.
o disruption of the aquaporin-2 shuttle and
o 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).

24. • 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.

25. 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

26. • 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

27. • 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.

28. 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.

29. – 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.

30. – 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.

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

32. 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.

33. • 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

34. 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%.

35. 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.

36. • 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.

37. 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).

38. 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.

39. • 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)

40. • 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.

41. ANTIANXIETY/SEDATIVE/HYPNOTICS
RELATED LIFE THREATENING SIDE
EFFECT
Dose Dependent Action
Sedation
(Sedative)
Sleep
(Hypnotic)
Anesthesia
(Anesthetic)
Coma Death

42. 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.

43. Signs and symptoms
1. Dizziness,Confusion,Drowsiness,Unresponsiveness,
Anxiety, and Agitation.
2. Blurred vision and Nystagmus.
3. Slurred speech, ataxia, Weakness.
4. Hypotension.
5. Respiratory depression.
6. Coma.

44. 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.

45. 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.

46. 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.

47. • 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.

48. 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.

49. THANK YOU