pharmacology and toxicology of antidepressants and antipsychotics

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Pharmacology and Toxicology of Pharmacology and Toxicology of Antidepressants and Antidepressants and

AntipsychoticsAntipsychoticsProf Ian Whyte FRACP, FRCP Edin

Hunter New England Toxicology Service


Traditional AntipsychoticsTraditional 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 AntipsychoticsNewer Antipsychotics

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


AntipsychoticsAntipsychotics


Differences among Differences among Antipsychotic DrugsAntipsychotic 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



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



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



Chlorpromazine: α1 = 5-HT2 > D2 > D1

Haloperidol: D2 > D1 = D4 > α1 > 5-HT2

Clozapine: D4 = α1 > 5-HT2 > D2 = D1


Metabolic effectsMetabolic effects

Weight gain over 1 year (kg)

aripiprazole 1

amisulpride 1.5

quetiapine 2 – 3

risperidone 2 – 3

olanzapine > 6

clozapine > 6


Insulin resistanceInsulin 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 elderlyStroke 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


ConclusionsConclusions 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 AntidepressantsTraditional 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 antidepressantsNewer 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 antidepressantsNewest 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)


Selectivity of Selectivity of antidepressantsantidepressants

0.001

0.01

0.1

1

10

100

1000 Nisoxetine

NomifensineMaprotiline (approx)

Desipramine

Imipramine Nortriptyline Amitriptyline

Clomipramine Trazodone Zimelidine

Fluoxetine

Citalopram (approx)

NA-selective

Non-selective

5-HT-selective R

atio

NA

: 5-

HT

upt

ake

inhi

biti

on


SSRINaRI

RIMA

NaSSA

NaSSA


Serotonin excessSerotonin 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 criteriaSternbach criteriaMental status changes (confusion, hypomania) Agitation Myoclonus Hyperreflexia Diaphoresis Shivering Tremor Diarrhoea Incoordination Fever

Diarrhoea


Serotonin receptorsSerotonin receptors

5–HT1

– subtypes 5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F

5–HT2

– subtypes 5–HT2A, 5–HT2B, 5–HT2C



5–HT3

5–HT4 (rat)

5–HT5 (rat) 5–HT5A, 5–HT5

5–HT6 (rat)

5–HT7 (rat and human)



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 drugsSerotonergic drugs

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



Serotonin re-uptake inhibitors– citalopram, fluoxetine, fluvoxamine,

paroxetine, sertraline, venlafaxine– clomipramine, imipramine– nefazodone, trazodone– chlorpheniramine– cocaine, dextromethorphan, pentazocine,

pethidine, tramadol



Serotonin agonists– fenfluramine, p–chloramphetamine– bromocriptine, dihydroergotamine,

gepirone– sumatriptan– buspirone, ipsapirone– eltoprazin, quipazine



Monoamine oxidase inhibitors (MAOIs)– clorgyline, isocarboxazid, nialamide,

pargyline, phenelzine, tranylcypromine– selegiline– furazolidone– procarbazine



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



Miscellaneous/mixed– lithium– lysergic acid diethylamide (LSD)– 3,4–methylenedioxymethamphetamine

(MDMA, ecstasy)– methylenedioxyethamphetamine (eve)– propranolol, pindolol


Serotonin excessSerotonin 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 excessSerotonin excess

Other responses to neuroexcitation– fever– rhabdomyolysis


Severe serotonin toxicitySevere serotonin toxicity

Combination therapy – multiple different mechanisms of serotonin

elevation Rapidly rising temperature Respiratory failure

– hypertonia/rigidity Spontaneous clonus


Treatment optionsTreatment options

Supportive care– symptom control– control of fever– ventilation

5–HT2A antagonists

– ideal safe effective available


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

CyproheptadineCyproheptadine

Oral preparation Safe 20–30 mg required to

achieve 90% blockade of brain 5–HT2 receptors

Cyproheptadine 100Chlorpromazine 71Chlorprothixene 233Haloperidol 2.8Clozapine 62Risperidone 170Olanzapine 25Sertindole 260Methysergide 14Ketanserin 178

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


ChlorpromazineChlorpromazine

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


TherapyTherapy

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


ConclusionsConclusions

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


ConclusionsConclusions

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

pharmacology and toxicology of antidepressants and antipsychotics

Documents