Adverse effects of antipsychotic drugs

Clinical pharmacology of antipsychotic drugs: adverse effects, drug interactions, poisoning

1. Adverseeffectsof
antipsychoticdrugs
Domina Petric, MD

2. Behavioraleffects
•Theoldertypicalantipsychoticdrugs
are unpleasantto take.
•Thiscanbemitigatedbygivingsmall
dosesduringthedayandthemajor
portionat bedtime.
•Pseudodepressionmaybedueto
drug-inducedakinesia: usually
respondsto treatmentwith
antiparkinsonismdrugs.

3. Behavioraleffects
•Otherpseudodepressionsmaybedue
to higherdosesthanneededina
partiallyremittedpatient: decreasing
thedosemayrelievethesymptoms.
•Toxic-confusionalstatesmayoccurwith
veryhighdosesofdrugsthathave
prominentantimuscarinicactions.

4. Neurologiceffects
Extrapyramidalreactionsoccurring
earlyduringtreatmentwitholder
agentsinclude:
•typicalParkinson´s syndrome
•akathisia(uncontrollable
restlessness)
•acutedystonicreactions(spastic
retrocollisor torticollis)

5. Neurologiceffects
•Parkinsonismcanbetreatedwith
conventionalantiparkinsonismdrugsof
theantimuscarinictypeor with
amantadine(rarely).
•Levodopashouldneverbeusedin
thesepatients!
•Parkinsonismmaybeself-limiting.
•Anattemptto withdrawantiparkinsonism
drugsshouldbemadeevery3-4 months.

6. Neurologiceffects
Akathisiaanddystonic
reactionsare besttreatedin
manycaseswithsedative
antihistaminewith
anticholinergicproperties
parenterallyor orally:
diphenhydramine.

7. Pinterest.com

8. Neurologiceffects
Tardivedyskinesia
•Itis a late-occurringsyndromeof
abnormalchoreoathetoidmovements.
•Itis themost importantunwantedeffect
ofantipsychoticdrugs.
•Itis probablycausedbya relative
cholinergicdeficiencysecondaryto
supersensitivityofdopaminereceptorsin
thecaudate-putamen.

9. Tardivedyskinesia
•Tardivedyskinesiais estimatedto have
occurredin20-40% ofchronicallytreated
patientsbeforetheintroductionofthe
neweratypicalantipsychotics.
•Earlyrecognitionis important!
•Advancedcasesmaybedifficultto
reverse.
•Quetiapineandclozapinehavetheleast
likelihoodofcausingtardivedyskinesia.

10. Tardivedyskinesia
•Anypatientwithtardivedyskinesiatreated
witha typicalantipsychoticdrug or possibly
risperidoneor paliperidoneshouldbe
switchedto quetiapineor clozapine.
•Thecourseofthedisorderis variableand
sometimesself-limited.
•First stepshouldbeto discontinueor
reducethedoseofthecurrent
antipsychoticagent or switchto
quetiapineor clozapine.

11. Tardivedyskinesia
•Secondstepwouldbeto eliminate
thedrugswithcentral
anticholinergicaction, particularly
antiparkinsonismdrugsandtricyclic
antidepressants.
•Theadditionofdiazepamindosesof
30-40 mg/daymayaddto the
improvementbyenhancing
GABAergicactivity.

12. Extrapyramidalsyndrome(EPS)
Akathisia
Canoccurearlyduring
treatment.
Tardivedyskinesia
Most important
unwantedeffect!
Parkinson´s syndrome
Shouldnotbetreated
withlevodopa!
Acutedystonicreactions
Canoccurearlyduring
treatment.
EPS

13. Neurologiceffects
Seizures
•De novo seizuresmayoccurin2-5%
ofpatientstreatedwithclozapine.
•Useofananticonvulsantis ableto
controlseizuresinmost cases.
•Seizurescanalsobea complication
ofchlorpromazinetreatment.

14. Autonomicnervoussystemeffects
•Most patientsare ableto tolerate
theantimuscarinicadverseeffectsof
antipsychoticdrugs.
•Thosepatientswhodevelopurinary
retentionor otherseveresymptoms
canbeswitchedto anagent without
significantantimuscarinicaction.

15. Autonomicnervoussystemeffects
•Orthostatichypotensionand
impairedejaculationare common
complicationsoftherapywith
chlorpromazineor mesoridazine.
•Thesepatientsshouldbeswitched
to drugswithlessmarked
adrenoreceptor-blockingactions.

16. Metabolicandendocrineeffects
•Weightgainis verycommon, especiallywith
clozapineandolanzapine.
•Thisrequiresmonitoringoffoodintake,
especiallycarbohydrates.
•Hyperglycemiamayalsodevelop, as wellas
hyperlipidemia.
•Themanagementofweightgain, insulin
resistanceandincreasedlipidsshouldinclude
monitoringofweightat eachvisitand
measurementoffastingbloodsugarand
lipidsat3-6 monthintervals.

17. Metabolicandendocrineeffects
Measurement of hemoglobin A1C
may be useful.
Diabetic ketoacidosis has been
reported in a few cases.
Thetriglyceride:HDL ratioshould
belessthan3,5 infastingsamples.

18. Metabolicandendocrineeffects
•Hyperprolactinemiainwomenresultsin
theamenorrhea-galactorrheasyndrome,
whichleadsto infertility.
•HyperPRLinmencauseslossoflibido,
impotenceandinfertility.
•HyperPRLmaycauseosteoporosis,
particularlyinwomen.
•AripiprazoledoesnotraisePRL
levels!

19. Toxic/allergicreactions
•Agranulocytosis, cholestaticjaundiceand
skineruptions…
•Clozapinecausesagranulocytosisina small,
but significantnumberofpatients: 1-2%.
•Agranulocytosiscandeveloprapidly, usually
betweenthe6th and18th weeksoftherapy.
•Patientsreceivingclozapinemust have
weeklybloodcountsfor thefirst6
monthsoftreatmentandevery3weeks
thereafter.

20. Ocularcomplications
Deposits in the anterior portions of the
eye (cornea, lens) are a common
complication of chlorpromazine therapy.
Thesedepositsmayaccentuatethe
normalprocessofagingofthelens.

21. Ocularcomplications
Thioridazine is the only antipsychotic drug that
causes retinal deposits.
Thesedepositsmayresembleinadvancedcases
retinitispigmentosa.
The deposits are usually associated with
browning of vision.
Themaximumdailydoseofthioridazineis
limitedto 800 mg/day.

22. Cardiactoxicity
•Thioridazineindosesexceeding300 mg
dailyis almostalwaysassociatedwith
minorabnormalitiesofT wavesthat
are easilyreversible.
•Overdosesofthioridazineare
associatedwithmajor ventricular
arrhythmias: torsadesde pointes,
cardiacconductionblockandsudden
death.

23. Cardiactoxicity
•Ziprasidonecarriesthegreatestriskof
QT prolongationandshouldnotbe
combinedwithotherdrugsthatprolong
theQTinterval: thioridazine, pimozide,
antiarrhythmicdrugs1A and3.
•Clozapineis sometimesassociatedwith
myocarditisandmust bediscontinued
ifmyocarditismanifests.

24. Pregnancy
Ifa pregnantwomancould
manageto befreeof
antipsychoticdrugsduring
pregnancy, thiswouldbe
desirablebecauseoftheireffects
on theneurotransmitters
involvedinneurodevelopment.

25. Neurolepticmalignantsyndrome
(NMS)
•Thislife-threateningdisorderoccursin
patientswhoare extremelysensitiveto
theextrapyramidaleffectsof
antipsychoticagents.
•Theinitialsymptomis markedmuscle
rigidity.
•Ifsweatingis impaired, fevermayensue,
reachingdangerouslevels: oftenwith
anticholinergicdrugs.

26. Neurolepticmalignantsyndrome
(NMS)
•Thestressleukocytosismayerroneously
suggestaninfectiousprocess.
•Autonomicinstability, withalteredblood
pressureandpulse rate, is oftenpresent.
•Muscle-typecreatinekinaselevelsare
usuallyelevated, reflectingmuscle
damage.
•Pathophysiology: excessivelyrapid
blockadeofpostsynapticdopamine
receptors.

27. Treatment
Muscle relaxants: diazepam, dantrolene…
Dopamine agonists, such as bromocriptine
Cooling measures
Switchingto anatypicaldrug after
recovery!

28. Drug interactions
II.

29. Drug interactions
•Antipsychoticsproducemore important
pharmacodynamicthanpharmacokinetic
interactions!
•Additiveeffectsmayoccurwhenthesedrugs
are combinedwithothersthathavesedative
effects, α-adrenoreceptorblockingaction
andanticholinergiceffects.
•Inthecaseofthioridazineandziprasidoneit
is importantnotto combinethesedrugswith
thosethathavequinidine-likeaction.

30. Overdose
III.

31. Overdose
•Poisoningswithantipsychoticagentsare
rarelyfatal, exceptwithMESORIDAZINE
andTHIORIDAZINE.
•Drowsinessproceedsto comawithan
interveningperiod ofagitation.
•Neuromuscularexcitabilitymaybe
increasedandproceedto convulsions.
•Pupilsare miotic.
•Deeptendonreflexesare decreased.

32. Overdose
•Hypotensionandhypothermiaare the
rule, althoughfevermaybepresent
laterinthecourse.
•Thelethaleffectsofmesoridazineand
thioridazineare relatedto inductionof
ventriculartachyarrhythmias.
•ABCD treatmentfor poisonings
andsupportivecare!

33. Overdose
Hypotension, hypothermia
FEVER laterinthecourse
Drowsiness
COMA withanintervening
period ofAGITATION
Neuromuscularexcitability
CONVULSIONS
MIOSIS
Decreaseddeeptendon
reflexes
Mesoridazine,
thioridazine
Other
agents
rarely
Ventricular
tachyarrhythmias
ABCD!

34. Psychosocialtreatmentand
cognitiveremediation
are veryimportantpartofthetherapy.

35. Literature
•Katzung, Masters, Trevor.
Basicandclinical
pharmacology.
•Pinterest.com