Antidepressants Flashcards
Discuss risk assessment of acute lithium toxicity
In the setting of normal renal fucntion acute ingestion of <25g is benign causing no more than minor GIT symptoms
Acute ingestion of >25g may cause more singificant GIT symptoms but rarley lead to significant neurotoxicity, provided that good supportive care is instituted so as to avoid dehydration, sodium depletion or renal impairment
Acute or chronic renal impairment of renal function, dehydration or sodium depletion significnatly impairs urinary lithium excretion
If the above are cocurrent with acute ingestion lithium ions are redistribtued to tissue compartments including the CNS instead of being excreted thus enhancing the potential for progressive onset of neurotoxicity
Discuss TK and TM of lithium
TM: Lithium is a monovalent cation primarily used in the management of bipolar disorder. Like most metal salts lithium carbonate acts as a direct irritant to the GI tract. Once absorbed lithium ions substitute for sodium and potassium and ar though to modulate intracellular secondary messengers. They may also affect neuotransmitter poruction and release
TK: Standard release lithium preps are normally completely absorbed within 6 hours of ingestion and peak serum lithium levels occur within 4 hours. Absorption may be prolonged in OD with peak leves delayed up to 12 hours with slow release preparations. Lithium is slowly redistributed from the intravascular compartment to tissue compartments including the CNS with a steady stae volume of 0.7-0.9L/kg. Elimination is almost enterily renal and clearnace is dependant on GFR and reduced in water or sodium deplete states.
Discuss clinal features of acute lithium
Small acute overdoes are often asymptomatic
- Larger overdose show nasuea vomiting abdominal pain and diarrhoea
- significant fluid loss may occur
Neuro
- if they develop they are delayed reflected slow redistribution to the CNS
- Tremor is the earliest sign - rarely progres past this evel as long as ecretion is miantained
- minor ST-T wave changes are observed
Discuss ix of acute lithium ovderose
Standard
EUC
-detect hyponatraemia or renal impairement
LIthium level
- confirm ingestion and monitor progress
- peak levels > 5mmol/L occur are not unusual
Discuss management of acute lithium overdose
Resus
- the patient who present late with severe GI symptoms requires fluid resus aiming for urine output of >1ml/kg/hour - normalisation of NA
- monitor fluid and electrolyte status
- telemtry
D: no indicatied
E: HD is effective however those with normal renal function whose hydration and sodium replacement are ensured benefit littler – reserved for established renal failure or those presenting late with established neuro signs
A: nil
D: - nil evidence of neurotoxicity and serum levels <2.5 can go home
Discuss risk assessment in chronic lithium overdose
Consider lithium intoxication in any pateint on lithium who presents with neurological signs of symptoms
- -signficant obtundation or seizure activity is an indication of severe toxicity that carries risk fo permanent neuro sequale
- serum lithium concentration correlate poorly with clincial feautres
Discuss IX of chornic lithium toxicity
Standard
Serum lithium
-good to confirm diagnosis and monitor paitent preogress
EUC
TFT
Be aware that neurolgoical sequale may persist long after levels return to normal
Discuss clinical features of chronic lithium toxicity
The clinical features are principally neurolgoical. The following classification by Hansen and Amdisen is widely used
Grade 1 (mild)
- tremor, hyperreflexia, agitation, msucle weakness ataxia
Grade 2(moderate)
- stupor, rigidity, hypertonia, hypotension
Grade 3 (severe)
-com, seizures, myclonus
GI symptoms are not prominent with chronic toxicity
The msot common cause of impaired lithium excretion are impaired renal fucntion, diabetes insipidius, sodium depletion, dehydration and drug interaction.
Drugs that impair lithium excretion include
- NSAIDS
- ACE
- Thiazides
- topiramate
Nephrogenic DI and hypothyroidism are associated with lithium tehraepy and can contribute to the development of toxicity and complcate the clinical presentation
Discuss management of chronic lithium toxicity
Resus – not usually required in the absence of siezures.
D: nil
E: HD - considered in patients with neuo dysfunction and a serum lithium level >2.5mmol/L
A: nil
Discuss risk assessement of mirtazapine, TM and TK and managmeent
Deliberate self poisoning with this novel tetracyclic antipdepressant usually follows a benign course with mild CNS depression and tachcardia Care is supportive
TM: mirtazapine is a centrally acting alpha 2 adrenrgic antagonist that enhances release of serotonin and norad. It alos acts as an antagonist at serotonin and histamine receptors
TK: Rapidaly absorbed
85% protein bound with a very large VD >100L/Kg
Hepatic metabolism with renal excretion
Mild tachy, htn and drowsiness may occur
CNS depression is more likley with infgestion of >1000mg but rarely enough to warrent ETT
Treatment is supportive with nil specific decontamination , elimination or antidote
Discuss risk assessment of MAOIs
Irreversible non selective MAO inhibtors are associated with potentially lethal serotonin toxicity in overdose, signficant adverse reaction and a withdrawal syndrome.
Irreversible non slective (phenelzine, tranycyprmine) Irreversible selective (MAO -B) - selegiline Reversible selecrtive (MAO A) moclobemide
Overdose of moclobemide alone causes minor symptoms only irrespective of dose
- non life threatening serotonin syndrome occurs in 5%
- QTc prolongtion >500ms may occur with infgestion >3g but torsades is not reported
- Coingestion with another serotonergic agent is assoicated with higher risk of severe serotonin syndrome
Phenelzine and tranylcypromine are associated with dose dependant potentially lethal serotonin and sympathomimetic toxicity, symptoms are delayed and prolonged
-Dos related risk with phenelzine
->2mg/kg associated with toxicity
-4-6 mg/kg potentially fatal
Dose related asssessment of tranylcypromine
->1mg/kg assocaited with tox
-170mg has caused fatality
CHildren 1-2 of phenelzine or tranycypromine can be associated with signifiacnt toxicity
Discuss TM and TK of MAOi
TM: MAOIs inhibit monoamine oxidase A and B in a selective or non selective reverisble or irreversible manner. MAO-A metabolises serotonin noradrenaline and dopamine. MAO-B metabolises phenylethylamine and benzylamine at central and peripheraln synaptic sites. Irreversible blockade requires new enzyeme synthesis over days to resatblish enzymatic function. Irreversible non selective agents in overdose lead to accumulation of serotonin adrenaline norad doapamine and phenylethylamine resulting in both serotonin and sympathomimetic toxicity that can persist for days
TK: All are well orall absobred with peak levels wihtin 2-3 horus. There is considerable first pass metbaolism. Moderate VD with hepatic metabolism and renal excretion.
Discuss clincial features of MAOI
Moclobemide overdose wihtout ingestion
- minor symptoms
- nausea anxiety and tachycardia may occur
- serotonin syndrome is rare
Phenelzine or tranylcypromine
- usually asymptomatic for the first 6-12 hours
- onset of toxicity is heralded by restlessness, agitation, tachycardia, involunatary movements clonus and hyperreflexia
- rapid decline in conscious state follows
- muscle rigiidy develops leading to resp compromise hypoxia, resp acidosis, hyperthermia and rhabdo
- Autonomic instability is demonstrated by swings from hypo to hypertension
- DIC and MOF may occur
- even with optimal supportive care intoxication may last several days
Classically described MAOI adverse reaction
- serotonin syndrome
- tyramine reaction - after the ingestion of a tyramine containing food (e.g cheese) patients complain of severe occiptal headache, asscoaited with pronounced HTN, sweating, agitation, mydriasis and somtimes chest pain- complications of HTN crises occur
Discuss IX of MAOI
ECG –> prolonged QTC
EUC, FBC, CK, TNI, ABG, CXR, CT head
Discuss management of MAOI od
Resus
- Serotonin syndreome and severe sympathomimetic toxicity are potentially life threatening
-HTN and tachy are usually controlled with titrated IV benzo, severe HTN may require vasodilator therapy - caution is required as the onset of autonomic instability may rapidly produce hypotension
—GTN or SNIP
—Phentolamine 2-3mg increments every 10-15 mintues
Seizure and hyperthermia should be managed
D: patient alert and co-operative with either tranylcypromine or phenelzine are treated with 50g charcoal if present within 2 hours
E: nil
A: cyprohepatadine is indicatated in patient with symptoms consistent with mild to moderate serotonin syndrome
Discuss risk assessment of olanazapine
Olanzapine overdose is associated with predictable does dependant clinical features
- EPS are uncommon
- coingestion of etoh or other sedative hyponotic agents increase the risk fo coma
Dose dependent affect
- <40mg - therapeutic sedation and antipsycotic effect
- 40-100mg mild to moderate sedation with possible anticholinergic effects
- 100-300 sedation with inermittent marked agitation
- > 300mg increased sedation progressive to coma likely to require intubation, hypotension secoandry to peripheral alpha blockade
Discuss TM and TK of olanzapine
TM - antagonist at dopamine (d2), serotonin, histamine, muscarinic and peripheral alpha receptors
TK: - well absorbed orally or sublingually
VD is 10-20L/KG
hepatic metbaolism via CP450
Large first pass effect with oral dosing
Discuss clinical features of olanzapine
Onset of clincal features of intoxication occur within 2-4 hours
- sedation ataxia, miosis, orthostatic hypotnesion and tachycardia are common
- fluctuating mental status with intermittent agitated delirium occurs with moderate doses usually lasting less than 24 hours, Urinary retention frequently complicates this presentation
- Coma when it occurs folloows large ingestions and last from 18-48 horus
- non specific ST-Twave changes occur but clinically signicaint QTC prolongation is rare
- EPS are rare
- Seizrue are rare
Discuss management of olanzapine overdose
REsus
Nil specific DEAD
All paeds patients are observed in hospital following unintentional ingestion of >0.5mg/kg. If they remian clinically well without sedation at 4 hours following ingestion they can be safely discharged home.
Discuss risk assessment of phenothiazines and butyrophenones
Phenothiazine: chlorpromazine, fuphenazine, prochlorperazine
Butyrophenones: droperidol and haloperidol
The antipsychotic (neurleptic) agents cause CNS depression, orthostatic hypotension, dystonias and anticholinergic effects
- Chlorpromazine can cause coma requiring inutbation and ventilation with ingestions >5g
- Cardiac dysrhythmias are very uncommon
- seizures are uncommon after any dose
Discuss TM and TK of phenothiazine and butyrophenones
TM: Phenothiazine is affect is mediated via central doapmine antagonism. THeir adverse effects are secondary tp antagpnist action at multiple receptors including H1, GABA , M1, A1 and 2 and 5HT. Cardiotoxicity is secondary to sodium and potassium blocakde. The butyrophenones are a seperate class of drug with similar TM
tK: radpialy absorbed following oral admin and undergo extensive first pass metabolissm with variable bioavailability.
Antispychotics are lipid soluble with large VD
They undergo extensive metabolism with Py450 and many ahve active metabolites with prolonged elimination half lifes. Chlorpromazine has early intermiedaite and late elimination phases
Discuss clinical features of phenothiazine and butyrophenones OD
-Onset of clincal features of intoxication occurs within -2-4 hours of overdose.
-Sedation ataxia orthostatic hypotension and -tachycardia are common
-FLuctuating mental status with intermittent agitated delirium may occur with moderate doses and usually last <24 hours
-urinary retention is common
-coma following large ingestion can last 18-48 hours
Anticholinergic delrium may complciated recovery from coma
-QT prolongation and torsades were chracteristic of thioridiazine OD but a not clinically signifiacnt with other currenty available agents
-Seizure and EPS are uncommon
Discuss management of phenothiazine and butyrophenones OD
RESUS
Supportive
D: activated charcoal if indicated is reserved until after ETT is placed due to risk of imminent coma
E: nil
A: nil
D: 6 hour observation if nil signs can be discharge home
Discuss risk assessment of quetiapine
2nd gen atypical antipsychotic - associated with sedation delirium coa tachycardia and hypotension in overdose. It is currently a leading cause of toxic coma requiring ICU
Predictable dose dependant CNS depression ranging from sedation to coma and a characteristic brisk tachycardia
-<3 G – mil to moderate sedation and sinus tachy >120BPM
>3 G - increasing risk of CNS depression coma and hypotension, Delirium and siezure may occur
Discuss TM and TK of quetiapine
Tm- antagonist at mesolinbic D2, 5ht, h1, m1 and peripehral a1
TK: rapidly but incompletely absorbed
lipid soluble highly protein bound wiht large VD
Hepatic and renal excretion
Discuss clinical features of quetiapine OD
Occurs wihtin 2-4 hours and may last 24-72 hours
- sedation and sinus tachy are common
- coma if it occurs usually lasts from 18-48 hours
- hypotension
- clinically signifiacnt QTC is rare and torsades is not reported
- seizures are rare
Discuss management of quetiapine OD
RESUS
-A if needed
C: if hypotension 20ml/kg crystaloid than pressor
D: - airway first if using charcoal
E: nil
a: Nil
D: Children are observed if >100mg/kg for 4 hours (8 if sustained) – advised for EPS symptoms for the next 72 hours
Discuss risk assessment of risperidone
Deliberate self poisoning with this atypical antipsyhcotic agent is asscoated with tachycardia and acute dysotnic reactions. CNS depression is unusual and rarely signifiacnt
The dose effect profile is not well defined
Common nclinical features of toxicity include sinus tachy (50%) and acute dystonia (10%)
-CNS depression is rare when risperidone is taken alone
Childrne >1mg is associated wtih clincial features
Discuss TM and TK of risperidone
TM: Antagonist at mesolimbic D2 5HT2a, A2 and a1 - much lower affinity for h1 and m1 than other antipsychotics in its class
TK: rapidaly absorbed after orall administaration
highly protein bound and has moderate VD
Hepatic metbaolism by oxidation to active metbaolites eliminated in the kidney
Discuss clinical features of risperidone
THe onset of features of intoxication is radid and usually occurs wihitn 4 hours
- sinus tachy is common
- mild sedation may be observed but is uncommon
- miosis and mydriasis are reported
- acute dystonias occur frequently
- QT prolognation may occur but torsades is not reported
List dystonic reactions
- Layryngeal dystonia — a rare but potentially life-threatening variant characterised by throat pain, dyspnea, stridor and dysphonia.
- Oculogyric crisis — rotatory eye movements or deviated gaze
- Blepharospasm and other facial spasms — spasm of the eyelids (unable to open eyes) or other facial muscles
- Buccolingual crisis — protruding or pulling sensation of the tongue
- Torticollis, antecollis or retrocollis — twisting of the neck, or the head forced forwards or backwards
- Torticopelvic crisis — abdominal rigidity and pain
- Scoliosis or lordosis — lateral flexion of the spine or extension.
-Opisthotonic crisis — spasm of the entire body characterised by back arching, flexion of the upper limbs and extension of the lower limbs.
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Other characteristics of acute dystonic reactions include:
-Mental status is generally unaffected, anxiety & agitation are common
-Vital signs are often normal but tachycardia, tachypnoea and diaphoresis may be present.
Discuss management of Risperidone overdose
RESUS
D: not routinely used
E: not clinically useful
A: benztropine may be required for Dystonias
Discuss risk assessment of SSRI
Citalopram, escitaopram, fluoxetine, paroexetine, sertraline
Deliberate self poisoning with the slective SSRI is common and usually follows a benign course.
Among the SSRI citalopram and escitaloipram appear to be unique in their ability to cause dose dependant QT prolongation
Serotonin syndrome is usually mild to moderate with isolated overdose and occurs in 20% of cases
- seizures in 4%
- ingestion of >600mg citalopram or >300mg of escitalpram is asscoaited with QT prolongation
Discuss TM and TK of SSRi
TM- SSRI enchance central cerotonergic neurotransmission by inhibiting reuptake. They have little affinity for other receptors
TK- rapid absorption following oral admin - protein bound and have large VD
- hepatic metbaolism to form less active water soluble metabolites
- Didesmethylcitalopram is the metbaolite thought to cause QTC prolongation
Discuss clinical features of SSRI
Most asymptomatic
Minor symtpoms usually being wihtin 4 hours and resolve wihtin 12 hours
-mild serotonin syndrome occurs in less than 20% and manifest as anxiety, treomr, tachy or bradycardia and mydriasis - severe serotonin syndrome does not occur without coingestion
-Seisures are uncommon and most stongly associated with citalopram or escitalopram
-QT prolongation with citalopram and escitalopram
Discuss IX of SSRI
Standard
- QT prolognation is described in citalopram and escitolparam
- > 600mg of escitalopram or 300 of citalopram a 12 lead at presenation and continued cardiac monitoring to monitor for risk of torsades
Discuss management of SSRI OD
Resus
- seizures
- serotonin syndrome
- torsades
D:alert and co-operative patients with >300 for citalopram and 600 for escitalopram wihtin 4 hours can have charcoal
e: nil
A: nl
D:
Discuss risk assessment of TCA
Amitriptyline, clomipramine, doexpin, imipramine
TCA poisoning remains a major cause of morbidiy and mortality. Leads to rapid onset of CNS and CVS toxicity
Ingestion of >10mg/kg is life threatening
- onset of severe toxicity usually occurs within 2 hours of ingesion
- seizure and myclonus are more common with dothiepin
<5mg/kg minimal symptoms
5-10mg - dorwsiness and mild anticholinergic effect
>10 potential for major effects (coma, hypotension, seizure and cardiac dysrhythmias) to occur wihtin 2- 4hous, anticholinergic often masked by coma
>30 mg/kg severe toxicity with ph dependant cardiotoxicity and coma expected to last > 24 hours
Discuss TM and TK of TCA
TM: noradrenaline and serotinin reuptake inhibitors and GABA a recpror blockers. Myocradial toxciity is chiefly due to blackade of inactivated fast sodium channels. Other toxic affects are mediated by m1, h1 and peripheral a1. They cause reversible inhibtion of potassium channels and direct myocardial depression unrelated to conduction abnormalities
TK: TCA are rapidly absorbed following oral admin with peak within 2 hours. TCA are highly bound to plasma and tissu proteins and ahve large VD.
Discuss clicnail features of TCA
CNS
- sedation adn coma usually precede CVS signs
- seizures
- delirium secondary to anticholinergic effects is often obscured by coma
CVS
- Sinus tachy and mild elevation in BP
-hypotension due to alpha blockade and impaired contractility
- broad complex tachydysrhythmias
broad complex bradycardia occurs pre-arrest
Anticholinergic
- can occur on presentation or be delayed and prolonged
- Agitation, restlessness delirium
- mydriasis
- dry warm flushed skin
- tachycardia urinary retention ileus
- myoclonic jerk
Discuss IX of TCA overdose
ECG:
- prlongation of QRS
- large terminal R in avR
- increase r/s ratio (0.7) in aVR
- QT prlongation is also noted secondary to potassium channel blocakde
QRS >100 is predicitve of seizure
QRS >160 is predictive of V-tach
Discuss management of TCA overdose
RESUS >10mg/kg
A: prompt intubation is indicated to avoid resp acidosis and aim for alkalosis
-prior to intubation ECG for QRS prolongation - if present bicarb 1-2mmol/kg until effect is seen as intubation will worsen acidosis and lead to ventricular tachycardia
B: nil
C: Ventricular dysrhytmias common
-sodium bicarb 100mmol every 1-2 minutes until restoration of pulse and narrowing of QRS
-cardioversion and defib unlikley to be effective
-lignocaine 1.5mg/kg IV is third line when pH is established at 7.5
-Type ia, amioderone and betablockers are all contraindicated
-Fluid bolus if hypotension than norad +- arenaline (0.05mic/kg/min -0.5mcg/kg/min)
D: -Seizure with benzo
D:for signifiacnt ingestion charcoal is indicated but not prior to securing airway
E: nil
A: sodibic as above
Discuss risk assessment of venlafaxine and desvenlafaxine
Venlafaxine and desvenlafaxine are potent SNRI. Venlafaxine OD is potentially life threatening, it frequently causes seizures and in very large ingestion, CVS toxicity.
14% of patients have seiuzures but the incidence is dose dependent - onset may be delayed up to 16 hours following OD
High dose of serotonin syndrome if any other serotonergic agents are co-ingested.
DOSE <1.5 g - risk fo seizure 5% 1.5-3 - 10% 3-4.5g ->30% risk of seizure 4-5-7g -> risk of seizure approaches 100%, hypotension and minor QRS QT prolognation >7 g - hypotension+ LV dysfunction
Discuss clinical features of venlafaxine
Onset of clinical features may be delated up to 6-12 hours
-Dysphoria, anxiety mydraisis sweating tremor clonus tachycardia and htn are common and may herald the onset of seizures
Seizures are generalised short duration and self limiting.
Coma is not a feature of venlafaxine intoxication
Serotonin sydnrome only develops if co-ingestion of other serotoninergic drug
Large dose venlafaxine may cause severe LV dysfucntion. Minor QRS and QT prolongation
Rhabdo and hypoglycaemia occasionally severe are reported infreqently after large OD
Discuss management of venlafaxine overdose
RESUS
- Benzo for agitation
- Hyperthemia
D: activated charcoal is administered to patients who are alert and co-operative and present within 2 hours following ingestion of >4.5 G of venlfaxine or desvenlafaxine.
