Psychopharmacology1 Anti Psychotic, Mood Stabilizer DR SEDDIGH.

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Psychopharmacology 1 Anti Psychotic , Mood Stabilizer DR SEDDIGH

Transcript of Psychopharmacology1 Anti Psychotic, Mood Stabilizer DR SEDDIGH.

Page 1: Psychopharmacology1 Anti Psychotic, Mood Stabilizer DR SEDDIGH.

Psychopharmacology 1

Anti Psychotic ,

Mood Stabilizer

DR SEDDIGH

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Classes of psychotropic medication

Antipsychotic medications Mood-stabilizing drugs Anti-anxiety medications Antidepressant medications Psychostimulants

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Antipsychotic

medications

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Antipsychotics:Diagnostic Indications

Psychiatric Schizophrenia Schizoaffective disorder Mood disorders with psychosis Delusional disorder

Nonpsychiatric Dementia/Delirium Psychosis secondary to a nonpsychiatric medical disorder Developmental disability with psychosis and/or aggression Tourette’s disorder Nausea, vomiting

4

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Antipsychotic Agents

Antipsychotic agents have two major groupsConventional antipsychotics

Block dopamine receptors

Atypical antipsychotics

Moderate blockade of dopamine receptors

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ANTIPSYCHOTICS

Pre-90’s– “Typical”, conventional, traditional neuroleptics,

major tranquilizors– Modeled on D2 antagonism– EPS/TD

Post-90’s– “Atypical”, novel, 2nd generation– Modeled on 5-HT2/D2 antagonism– Less EPS, prolactin effects– Weight gain, sedation, diabetes

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Impact of antipsychotics..

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Conventional Antipsychotic Agents Classification

– Low potency-Thioridazine– Medium potency-perphenazine– High potency-Halopridol

Mechanism of Action– Block receptors of dopamine, acetycholine,

histamine, norepinephrine

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Typical antipsychotics– Phenothiazines

• e.g. chlorpromazine, fluphenazine, thioridazine

– Butyrophenones • e.g. haloperidol, droperidol

– Thioxanthines• e.g. chlorprotixen, thiothixene

Atypical antipsychotics

Clozapin

Risperidone

Olonzapin

Sertindole

Quetiapine

Classification of antipsychotic drugs

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Overview of Antipsychotics

Conventional AntipsychoticsChem. Group Generic Name Trade Mark Dose (mg)

Phenothiazines

chlorpromazine LARGACTIL, MEGAPHEN,

200-800

thioridazine MELLERIL 100-600

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Overview of Antipsychotics

Conventional AntipsychoticsChem. Group Generic Name Trade Mark Dose (mg)

Phenothiazines

Perphenazine PERFENAZIN, TRILAFON, PERATSIN

16-24

Prochlorperazine PROCHLORPERAZIN, STEMETIL

20-80

Fluphenazine MODITEN 2-16

trifluoperazine STELAZIN 10-50

Thioxanthenes flupenthixol FLUANXOL 6-18

Butyrophenoneshaloperidol HALOPERIDOL,

HALDOL, APO-HALOPERIDOL

2,5-10

melperone BURONIL 50-300

Diphenylbutylpiperidines

pimozide ORAP 2-10

fluspirilen IMAP 2-10

penfluridol SEMAP 2-60

Perathiepines oxyprothepin MECLOPIN 5-20

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Antipsychotics of the 2nd Generation

Generic Name Trade Mark Dose (mg)

D2, D3 selective antagonists

sulpiride DOGMATIL, PROSULPIN 50-1200

amisulpride SOLIAN, DENIBAN 50-1200

SDA

risperidone RISPERDAL, RISPEN, RISPERDAL QUICKLET

4-8

ziprasidone ZELDOX 40-160

Sertindole SERDOLECT 12-20

MARTA

clozapine LEPONEX 200-600

olanzapine ZYPREXA i.m. inj. 10 mg 5-20

quetiapine SEROQUEL 300-600

zotepine ZOLEPTIL 75-300

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Adverse Effects Summary

Sedation ‑ initially considerable; tolerance usually develops after a few weeks of therapy; dysphoria

Postural hypotension ‑ results primarily from adrenergic blockade; tolerance can develop

Anticholinergic effects ‑ include blurred vision, dry mouth, constipation, urinary retention; results from muscarinic cholinergic blockade

Endocrine effects ‑ increased prolactin secretion can cause galactorhea; results from antidopamine effect

Hypersensitivity reactions ‑ jaundice, photosensitivity, rashes, agranulocytosis can occur

Idiosyncratic reactions ‑ malignant neuroleptic syndromeWeight gain Neurological side effects - see next

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REACTION FEATURES TIME OF MAXIMAL RISK

PROPOSED MECHANISM

TREATMENT 

Acute dystonia Spasm of muscles of tongue, face, neck, back; may mimic seizures; not hysteria

1 to 5 days Unknown Antiparkinsonian agents are diagnostic and curative

 

Akathisia Motor restlessness; not anxiety or "agitation"

5 to 60 days Unknown Reduce dose or change drug: antiparkinsonian agents,b benzodiazepines or propranololc may help

 

Parkinsonism Bradykinesia, rigidity, variable tremor, mask facies, shuffling gait

5 to 90 days Antagonism of dopamine

Antiparkinsonian agents helpful  

Neuroleptic malignant syndrome

Catatonia, stupor, fever, unstable blood pressure, myoglobinemia; can be fatal

Weeks; can persist for days after stopping neuroleptic

Antagonism of dopamine may contribute

Stop neuroleptic immediately: dantrolene or bromocriptined may help: antiparkinsonian agents not effective

 

Perioral tremor ("rabbit" syndrome)

Perioral tremor (may be a late variant of parkinsonism)

After months or years of treatment

Unknown Antiparkinsonian agents often help

 

Tardive dyskinesia

Oral-facial dyskinesia; widespread choreoathetosis or dystonia

After 6 months or years of treatment (worse on withdrawal)

Excess function of dopamine hypothesized

Prevention crucial; treatment unsatisfactory

 

a. Many drugs have been claimed to be helpful for acute dystonia. Among the most commonly employed treatments are diphenhydramine hydrochloride, 25 or 50 mg intramuscularly, or benztropine mesylate, 1 or 2 mg intramuscularly or slowly intravenously, followed by oral medication with the same agent for a period of days to perhaps several weeks thereafter. b. For details regarding the use of oral antiparkinsonian agents, see the rest of slides c. Propranolol often is effective in relatively low doses (20-80 mg per day). Selective beta1-adrenergic receptor antagonists are less effective. d. Despite the response to dantrolene, there is no evidence of an abnormality of Ca2+ transport in skeletal muscle; with lingering neuroleptic effects, bromocriptine may be tolerated in large doses (10-40 mg per day).

Neurological Side Effects of antipsychotics

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Phenothiazines - Side effects

Weight gain – 40% - weight gain now attributed to ratio of binding to D2 and 5-HT2 receptors; possibly also histamine (for newer antipsychotics anyway)

Sexual dysfunction

• result from NE and SE blockade

• erectile dysfunction in 23-54% of men

• retrograde ejaculation in

• loss of libido and anorgasmia in men and women

Seizures - <1% for generalized grand mal

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ESTIMATED MEAN WEIGHT GAIN AT 10 WEEKS ESTIMATED MEAN WEIGHT GAIN AT 10 WEEKS

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Phenothiazines - Side effects

Neuroleptic malignant syndrome (1-2% early in trt)

• combination of motor rigidity, hyperthermia, and autonomic dysregulation of blood pressure and heart rate (both go up)

• can be fatal in 5-20% of cases if untreated

• treatment – discontinue meds; give trts for fever and cardiac problems

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Sensitivity to sun

• some phenothiazines collect in skin (chlorpromazine)

• sunlight causes pigmentation changes – grayish-purple splotching (look bruised)

• can also occur in eye and cause brown in cornea(chlorpromazine) and retin (thioridazine)

Jaundice – elevated bilirubin in liver - < ½%

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Limitations Of Conventional Antipsychotics

Approximately one-third of patients with schizophrenia fail to respond

Limited efficacy against– Negative symptoms– Affective symptoms– Cognitive deficits

High proportion of patients relapse

Side effects and compliance issues

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Antipsychotic Drugs – New Generations „atypical“

clozapine risperidone olanzapine sertindole quetiapine etc.

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Atypical antipsychotics

MARTA (multi acting receptor targeted agents) clozapine, olanzapine, quetiapine

SDA (serotonin-dopamine antagonists) risperidone, ziprasidone, sertindole

Selective D2/D3 antagonists sulpiride, amisulpiride

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Clozapine (1989)

Selectively blocks dopamine D2 receptors, avoiding nigrostriatal pathway

Also blocks NE

More strongly blocks 5-HT2 receptors in

Among non-responders to first generation meds

or those who cannot tolerate side effects, about 30% do respond to Clozapine

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Clozapine

Extrapyramidal side effects are minimal

May help treat tarditive dyskinesia

Still shows orthostatic hypotension effects, sedation, weight gain, increased heart rate

Increased risk for seizures (2-3%)

Agranulocytosis in 1%

Agranulocytosis risks increase when co-administered with carbamazepine

Interactions with SSRIs and valproic acid increase Clozapine levels and risks

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Risperidone (Risperdal; 1994)Fewer side effects than Clozapine

Marketed as first line approach to treatment

Blocks selective D2, norepinephrine, and 5-HT2

Argued as effective for positive and negative symptoms (controversial)

Extrapyramidal side effects low (but are shown at high doses) - controversial

Shares sedation, weight gain, rapid heart beat, orthostatic hypotension, and elevated prolactin

No agranulocytosis risks

May cause anxiety/agitation (possible OCD)

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Olanzipine - Zyprexa – 1996

• Same poorly supported arguments about improved negative symptom reduction

• Argued to be better than risperidone in extrapyramidal issues

• Does not cause prolactin elevation

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Sertindole – Serlect – 1995

• concern about sudden cardiac death or episodes due to cardiac arrhythmia led to its voluntary removal in 1998

Quetiapine – Seroquel - 1997

in IranZiprasidone – 2001

Similar to advantages of others, but argued not to cause weight gain

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HaloperidolHaloperidol ClozapineClozapine RisperidoneRisperidone OlanzapineOlanzapine

QuetiapineQuetiapine ZiprasidoneZiprasidone

5HT2A D2 D1 Alpha 1 Musc H1 5HT1A (agonist)

Casey 1994Casey 1994

Atypical Antipsychotics In Vivo Binding Affinities

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Mood StabilizersMood Stabilizers

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Mood StabilizersMood Stabilizers

LithiumLithium AnticonvulsantsAnticonvulsants

– Valproic Acid [Depakote]Valproic Acid [Depakote]– Carbamazepine [Tegretol]Carbamazepine [Tegretol]– New Anticonvulsants (?):New Anticonvulsants (?):

• Lamotrigine [Lamictal]Lamotrigine [Lamictal]• Topiramate [Topamax]Topiramate [Topamax]• Gabapentin [Neurontin]Gabapentin [Neurontin]

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LithiumLithium

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Lithium: HistoryLithium: History Used since mid-XIX: gout, diabetes...Used since mid-XIX: gout, diabetes... For BP since 1960’s, FDA ‘74For BP since 1960’s, FDA ‘74 Effective Antimanic, mood stab, BP depr.Effective Antimanic, mood stab, BP depr. If Discontinued relapse near 100% 2 yrIf Discontinued relapse near 100% 2 yr Therapeutic Levels:Therapeutic Levels: 1-1.5 mEq/ml 1-1.5 mEq/ml Acute maniaAcute mania 0.4-0.8 mEq/ml 0.4-0.8 mEq/ml MaintenanceMaintenance

0.3-0.8 0.3-0.8 mEq/ml mEq/ml in elderlyin elderly

– Narrow therapeutic indexNarrow therapeutic index

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Lithium: PharmacologyLithium: Pharmacology

Not Not liver liver metabolized. metabolized. KidneyKidney excreted excreted Not Not proteinprotein bound bound 70-80% reabsorb prox Tubule, 70-80% reabsorb prox Tubule,

Na (dehydr, thiazide diuret) Na (dehydr, thiazide diuret) Li levelLi level ExcretionExcretion related to GFR: related to GFR:elder elder pregpreg Half-lifeHalf-life 24 hrs (HS), steady state 5 days 24 hrs (HS), steady state 5 days Peak LevelsPeak Levels 2 hrs, SR 4-4.5 2 hrs, SR 4-4.5

– fast release: N/V, slow rel: diarrheafast release: N/V, slow rel: diarrhea

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Predictors: Good Li ResponsePredictors: Good Li Response

Past Li response (personal or family)Past Li response (personal or family) Euphoric, pure (classic) mania Euphoric, pure (classic) mania Sequence Mania-Depr-EuthymiaSequence Mania-Depr-Euthymia No psychosisNo psychosis No Rapid CyclingNo Rapid Cycling

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Predictors: Poor Li ResponsePredictors: Poor Li Response[Good response to anticonvulsants][Good response to anticonvulsants]

Mixed mania (adolescents)Mixed mania (adolescents) Irritable maniaIrritable mania Secondary mania (geriatric)Secondary mania (geriatric) Psychotic SxPsychotic Sx Rapid CyclingRapid Cycling Depression-Mania-EuthymiaDepression-Mania-Euthymia Comorbid substance abuseComorbid substance abuse

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Lithium: Lithium: CommonCommon Side Effects Side Effects

GI distressGI distress Polyuria / polydipsiaPolyuria / polydipsia Sedation-lethargySedation-lethargy Cognitive (memory, concentr, slow)Cognitive (memory, concentr, slow) Wt. GainWt. Gain Poor coordination, tremorPoor coordination, tremor Skin (worse acne)Skin (worse acne)

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Lithium: Lithium: SeriousSerious SE SE Renal Renal

– nephrogenic diabetes insipidusnephrogenic diabetes insipidus– tubular interstitial nephritistubular interstitial nephritis

HypothyroidismHypothyroidism Psoriasis (onset or worsening)Psoriasis (onset or worsening) Cardiac: EKG flat T, SA dysfx, Cardiac: EKG flat T, SA dysfx,

tachicardiatachicardia Li ToxLi Tox. N/V/D, delirium, ataxia, stupor. N/V/D, delirium, ataxia, stupor

– Tx dyalisis if >3.0, correct fluid-electrolitesTx dyalisis if >3.0, correct fluid-electrolites

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Li: Interactions & UseLi: Interactions & Use

Li levels: Li levels: • diuretics, diuretics, • NSAIDs (ASA, sulindac OK)NSAIDs (ASA, sulindac OK)• ACE-inhibitorsACE-inhibitors

Starting:Starting:– Baseline Renal, TFT, HCG, EKG >40yo, Baseline Renal, TFT, HCG, EKG >40yo,

UA, weight, medical Hx UA, weight, medical Hx – 300-600 mg/day divided doses300-600 mg/day divided doses– Levels in 5 daysLevels in 5 days– Increase 900-1200 mg/day Increase 900-1200 mg/day

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Valproate NAValproate NA

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Valproate [Depakote]Valproate [Depakote]

FDA Sz ‘78, BP ‘96FDA Sz ‘78, BP ‘96 Effective antimanic, BP depressionEffective antimanic, BP depression Therapeutic effect 2 d. level 50-125 Therapeutic effect 2 d. level 50-125

mg/lmg/l– oral loading 20-30 mg/kg/dayoral loading 20-30 mg/kg/day

Mixed, rapid cycling, schizoaffectiveMixed, rapid cycling, schizoaffective Closed had injury, EEG abnormalityClosed had injury, EEG abnormality

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VPA: VPA: CommonCommon Side Effects Side Effects GI distressGI distress SedationSedation Liver transaminase elevationLiver transaminase elevation TremorTremor Hair lossHair loss Weight gain-increased appetiteWeight gain-increased appetite Thrombocitopenia (eldersThrombocitopenia (elders) Teratogenic: neural tube, cranio-facial

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VPA: VPA: LessLess Common SE Common SE

NeutropeniaNeutropenia Coagulopathies, Coagulopathies, platelet Functionplatelet Function endocrine abnormalitiesendocrine abnormalities

– Amenorrhea, policystic ovary?Amenorrhea, policystic ovary?– HypothyroidismHypothyroidism– HypocortisolemiaHypocortisolemia

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VPA: VPA: Rare DangerousRare Dangerous SE SE Idiosincratic Hepatic FailureIdiosincratic Hepatic Failure

– lethargy, anorexia, N/V, jaund, bleed, edemalethargy, anorexia, N/V, jaund, bleed, edema– Risk: <3 y.o., many anticonvuls, Dev. DelayRisk: <3 y.o., many anticonvuls, Dev. Delay– Remote risk in >10yo psychiatric patientsRemote risk in >10yo psychiatric patients

Acute Hemorrhagic PancreatitisAcute Hemorrhagic Pancreatitis - Eatly 6 month,serum amylase level- Eatly 6 month,serum amylase level Bone Marrow SupressionBone Marrow Supression

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VPA UseVPA Use Baseline:Baseline:

– Medical Hx, CBC-diff, LFT (LDH, SGOT, Medical Hx, CBC-diff, LFT (LDH, SGOT, SGPT, bili, Alk. Phos, GGT), HCG, SGPT, bili, Alk. Phos, GGT), HCG, PT,PTT if bleeding abnorm, amylase?PT,PTT if bleeding abnorm, amylase?

– Warn about hepatic, pancreatic, Warn about hepatic, pancreatic, hematologic, teratogenic riskshematologic, teratogenic risks

Monitor LFT, CBCMonitor LFT, CBC

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CarbamazepineCarbamazepine

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Carbamazepine [Tegretol]Carbamazepine [Tegretol]

FDA Trig Neuralg ‘68, TLE ‘74FDA Trig Neuralg ‘68, TLE ‘74 Effective antimanic, Tx-refract DeprEffective antimanic, Tx-refract Depr Onset 2 wks, antidepr 4-6 wkOnset 2 wks, antidepr 4-6 wk Ther. Levels: 4-12Ther. Levels: 4-12 Half life decreases to 12-17 hrsHalf life decreases to 12-17 hrs

– p450 liver inductionp450 liver induction

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CBZ: Side EffectsCBZ: Side Effects

Less cognitive probl than LiLess cognitive probl than Li Less Wt gain, hair loss, tremor than VPALess Wt gain, hair loss, tremor than VPA Neuro: Diplopia,blurr vision, fatigue/sedNeuro: Diplopia,blurr vision, fatigue/sed GI: Naus/diarr, Dry mouthGI: Naus/diarr, Dry mouth Leukopenia, thrombocitopenia, rashLeukopenia, thrombocitopenia, rash LFTLFT Agranulocytosis (, Liver fail, pancreatitis, Agranulocytosis (, Liver fail, pancreatitis,

Stevens-JohnsonStevens-Johnson (exfol skin), (exfol skin), neuroteratogenicneuroteratogenic

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CBZ: UseCBZ: Use Baseline: Medical Hx, CBC+diff,LFT, Baseline: Medical Hx, CBC+diff,LFT,

Renal, TFT, HCG, ferritinRenal, TFT, HCG, ferritin Start low:Start low:

– 100-400 mg/day, 100-400 mg/day, 100-200 mg every several days, bid 100-200 mg every several days, bid

(occasionally qd)(occasionally qd) Follow CBC, LFTFollow CBC, LFT

– clinical monitoring more effective than clinical monitoring more effective than labslabs

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And Others …And Others … New AnticonvulsantsNew Anticonvulsants

• LamotrigineLamotrigine: ?Effective BP & depr, : ?Effective BP & depr, 10%rash, levels 10%rash, levels by CBZ, by CBZ, by VPAby VPA

• TopiramateTopiramate: wt loss, 1.5% renal stones: wt loss, 1.5% renal stones• GabapentinGabapentin: effective?? (open reports, add-: effective?? (open reports, add-

on)on)• TiagabineTiagabine, , VigabatrilVigabatril Ca Ca

Others:Others:• Ca-channelCa-channel blockers blockers• TamoxifenTamoxifen Prot Kinase-C inhibitor Prot Kinase-C inhibitor

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THANKS FOR YOUR ATTENTION