Pharmacology and Toxicology of Antidepressants and Antipsychotics_Whyte


Pharmacology and Toxicology of Antidepressants and Antipsychotics
Prof Ian Whyte FRACP, FRCP Edin
Hunter New England Toxicology Service

Traditional Antipsychotics
Phenothiazines
–chlorpromazine (Chlorpromazine Mixture, Chlorpromazine Mixture Forte, Largactil)
–fluphenazine (Anatensol, Modecate)
–flupenthixol (Fluanxol)
–pericyazine (Neulactil)
–pimozide (Orap)
–thioridazine (Aldazine)
–trifluoperazine (Stelazine)
–zuclopenthixol (Clopixol)
Butyrophenones
–droperidol (Droleptan Injection)
–haloperidol (Haldol, Serenace)

Newer Antipsychotics

Atypical agents
–aripiprazole (Abilify)
–clozapine (CloSyn, Clopine, Clozaril)
–risperidone (Risperdal)
–quetiapine (Seroquel)
–amisulpride (Solian)
–olanzapine (Zyprexa)

Differences among Antipsychotic Drugs

All effective antipsychotic drugs block D2 receptors
Chlorpromazine and thioridazine
–block α1 adrenoceptors more potently than D2 receptors
–block serotonin 5-HT2 receptors relatively strongly
–affinity for D1 receptors is relatively weak
Haloperidol
–acts mainly on D2 receptors
–some effect on 5-HT2 and α1 receptors
–negligible effects on D1 receptors
Pimozide and amisulpride†
–act almost exclusively on D2 receptors

Differences among Antipsychotic Drugs

Clozapine
–binds more to D4, 5-HT2, α1, and histamine H1 receptors than to either D2 or D1 receptors
Risperidone
–about equally potent in blocking D2 and 5-HT2 receptors
Olanzapine
–more potent as an antagonist of 5-HT2 receptors
–lesser potency at D1, D2, and α1 receptors
Quetiapine
–lower-potency compound with relatively similar antagonism of 5-HT2, D2, α1, and α2 receptors

Differences among Antipsychotic Drugs

Clozapine, olanzapine and quetiapine
–potent inhibitors of H1 histamine receptors
–consistent with their sedative properties
Aripiprazole
–partial agonist effects at D2 and 5-HT1A receptors

Differences among Antipsychotic Drugs

Chlorpromazine: α1 = 5-HT2 > D2 > D1
Haloperidol: D2 > D1 = D4 > α1 > 5-HT2
Clozapine: D4 = α1 > 5-HT2 > D2 = D1

Metabolic effects Weight gain over 1 year (kg)aripiprazole

1
 
1.5
quetiapine
2 – 3
risperidone
2 – 3
olanzapine
> 6
clozapine
> 6

Insulin resistance

Prediabetes (impaired fasting glycaemia) has ~ 10% chance / year of converting to Type 2 diabetes
Prediabetes plus olanzapine has a 6-fold increased risk of conversion
If olanzapine is stopped 70% will revert back to prediabetes

Stroke in the elderly

Risperidone and olanzapine associated with increased risk of stroke when used for behavioural control in dementia
Risperidone 3.3% vs 1.2% for placebo
Olanzapine 1.3% vs 0.4% for placebo
However, large observational database studies
–Show no increased risk of stroke compared with typical antipsychotics or untreated dementia patients

Conclusions

Atypical antipsychotics have serotonin blocking effects as well as dopamine blockade
As a group have less chance of extrapyramidal side effects
Most have weight gain and insulin resistance as a side effect (except perhaps aripiprazole and maybe amisulpride)
May be associated with stroke when used for behavioural control in dementia
Many have idiosyncratic toxicities

Traditional Antidepressants

Tricyclic antidepressants
–amitriptylline (Endep, Tryptanol)
–clomipramine (Anafranil, Chem mart Clomipramine, GenRx Clomipramine, Placil, Terry White Chemists Clomipramine)
–doxepin (Deptran, Sinequan)
–dothiepin (Dothep, Prothiaden)
–imipramine (Tofranil)
–nortriptylline (Allegron)
–trimipramine (Surmontil)
Tetracyclic antidepressants
–Mianserin (Lumin, Tolvon)
MAOIs (monoamine oxidase inhibitors)
–Phenelzine (Nardil)
–Tranylcypromine (Parnate)

Newer antidepressants

SSRIs (specific serotonin reuptake inhibitors)
–citalopram (Celapram, Chem mart Citalopram, Ciazil, Cipramil, GenRx Citalopram, Talam, Talohexal, Terry White Chemists Citalopram)
–escitalopram (Lexapro)
–fluoxetine (Auscap 20 mg Capsules, Chem mart Fluoxetine, Fluohexal, Fluoxebell, Fluoxetine-DP, GenRx Fluoxetine, Lovan, Prozac, Terry White Chemists Fluoxetine, Zactin)
–fluvoxamine (Faverin, Luvox, Movox, Voxam)
–paroxetine (Aropax, Chem mart Paroxetine, GenRx Paroxetine, Oxetine, Paxtine, Terry White Chemists Paroxetine)
–sertraline (Chem mart Sertraline, Concorz, Eleva, GenRx Sertraline, Sertraline-DP, Terry White Chemists Sertraline, Xydep, Zoloft)
RIMA (reversible inhibitor of monoamine oxidase A)
–moclobemide (Arima, Aurorix, Chem mart Moclobemide, Clobemix, GenRx Moclobemide, Maosig, Mohexal 150 mg, Terry White Chemists Moclobemide)

Newest antidepressants

SNRI (serotonin noradrenergic reuptake inhibitors)
–venlafaxine (Efexor-XR)
NaSSA (noradrenergic and specific serotonergic antidepressant)
–mirtazapine (Avanza, Avanza SolTab, Axit, Mirtazon, Remeron)
NaRI (selective noradrenaline reuptake inhibitor )
–reboxetine (Edronax)

Serotonin excess

Oates (1960) suggested excess serotonin as the cause of symptoms after MAOIs with tryptophan
Animal work (1980s) attributed MAOI/pethidine interaction to excess serotonin
Insel (1982) often quoted as describing the serotonin syndrome
Sternbach (1991) developed diagnostic criteria for serotonin syndrome

Sternbach criteria

Mental status changes (confusion, hypomania) Agitation, Myoclonus, Hyperreflexia, Diaphoresis, Shivering, Tremor, Diarrhoea, Incoordination, Fever.

Serotonin receptors

5–HT1
–subtypes
5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F
5–HT2
–subtypes
5–HT2A, 5–HT2B, 5–HT2C

Serotonin receptors

5–HT3
5–HT4 (rat)
5–HT5 (rat)
5–HT5A, 5–HT5
5–HT6 (rat)
5–HT7 (rat and human)

Serotonin receptors

5–HT1
–subtypes
5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F
–primarily responsible for the therapeutic (antidepressant) effects of increased intrasynaptic serotonin
5–HT2
–subtypes
5–HT2A, 5–HT2B, 5–HT2C
–primarily responsible for the toxic effects of increased intrasynaptic serotonin

 Boyer EW, Shannon M
The serotonin syndrome
New England Journal of Medicine
2005 Mar 17;352(11):1112-20
 Isbister GK, Buckley NA
The Pathophysiology of Serotonin
Toxicity in Animals and Humans:
Implications for Diagnosis and
Treatment
Clinical Neuropharmacology
2005;28(5):205-214

Serotonergic drugs

Serotonin precursors
–S–adenyl–L–methionine
–L–tryptophan
–5–hydroxytryptophan
–dopamine

Serotonergic drugs
Serotonin re-uptake inhibitors
–citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine
–clomipramine, imipramine
–nefazodone, trazodone
–chlorpheniramine
–cocaine, dextromethorphan, pentazocine, pethidine, tramadol

Serotonergic drugs
Serotonin agonists
–fenfluramine, p–chloramphetamine
–bromocriptine, dihydroergotamine, gepirone
–sumatriptan
–buspirone, ipsapirone
–eltoprazin, quipazine

Serotonergic drugs
Monoamine oxidase inhibitors (MAOIs)
–clorgyline, isocarboxazid, nialamide, pargyline, phenelzine, tranylcypromine
–selegiline
–furazolidone
–procarbazine

Serotonergic drugs
Reversible inhibitors of MAO (RIMAs)
–brofaramine
–befloxatone, toloxatone
–moclobemide

Serotonergic drugs
Miscellaneous/mixed
–lithium
–lysergic acid diethylamide (LSD)
–3,4–methylenedioxymethamphetamine (MDMA, ecstasy)
–methylenedioxyethamphetamine (eve)
–propranolol, pindolol

Serotonin excess
Primary neuroexcitation (5–HT2A)
–mental status
agitation/delirium
–motor system
clonus/myoclonus
–inducible/spontaneous/ocular
tremor/shivering
hyperreflexia/hypertonia
–autonomic system
diaphoresis/tachycardia/mydriasis

Serotonin excess
Other responses to neuroexcitation
–fever
–rhabdomyolysis

Severe serotonin toxicity

Combination therapy
–multiple different mechanisms of serotonin elevation
Rapidly rising temperature
Respiratory failure
–hypertonia/rigidity
Spontaneous clonus

Treatment options

Supportive care
–symptom control
–control of fever
–ventilation
5–HT2A antagonists
–ideal
safe
effective
available

Treatment options

Supportive care
–symptom control
–control of fever
–ventilation
5–HT2A antagonists
–ideal
safe
effective
available

Cyproheptadine
 Oral preparation
 Safe
 20–30 mg required to
achieve 90% blockade
of brain 5–HT2
receptors

Cyproheptadine 100
Chlorpromazine 71
Chlorprothixene 233
Haloperidol 2.8
Clozapine 62
Risperidone 170
Olanzapine 25
Sertindole 260
Methysergide 14
Ketanserin

Affinity at 5-HT2 = 10-7 x 1/Kd

 Kapur, S et al. (1997). Cyproheptadine: a potent in vivo
serotonin antagonist. American Journal of Psychiatry, 154, 884

Chlorpromazine
5–HT2 antagonist
–PET scans show avid 5–HT2 binding
Oral or parenteral medication
–ventilated patients
–impaired absorption
recent activated charcoal
Sedating and a potent vasodilator

Therapy
Oral therapy
–cyproheptadine 12 mg stat then 4–8 mg q 4–6h
Oral therapy unsuitable or fails
–chlorpromazine 25–50 mg IVI stat then up to 50 mg orally or IVI q6h
Ventilation impaired and/or fever > 39oC
–anaesthesia, muscle relaxation ± active cooling
–chlorpromazine 100–400 mg IMI/IVI over first two hours

Conclusions
Serotonin toxicity is a spectrum disorder not a discrete syndrome
The clinical manifestations of toxicity are 5–HT2 mediated while the therapeutic effect is 5–HT1
Newer agents with little or no risk of serotonin toxicity
–Reboxetine and mirtazapine

Conclusions
First line of treatment is to remove the offending agent(s)
Specific inhibitors of 5–HT2 have a role but paralysis and ventilation may be needed

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1 Komentar (+add yours?)

  1. odasamodra
    Jan 22, 2013 @ 02:59:14

    pelajaran perkuliahan psikofasrmakologi yang sama dapat kan sangat membantu saya dalam meilah dan mengetahui manfaat dan kegunaan obat-obatan

    Balas

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