CHEMICAL TRANSMISSION DRUG ACTION IN THE CNS

Ján Mojžiš

P.J. Šafárik University

Faculty of Medicine

Department of Pharmacology

Košice

Neurotransmiters

Noradrenaline

Acetylcholine

Dopamine

Serotonin

GABA

Glutamate

Aspartate

Noradrenaline

relatively large amount of NA hypothalamus and limbic system

also present in other brain region

Receptors: 1A-C, 2A-C, 1, 2, 3

depression (deficiency of NA)

mania (excess of NA)

Acetylcholine

ACh - widely distributed in the brain

Receptors: N, M1-5

some M-receptors act presynaptically ACh release M-antagonists ACh release little information about function of N-receptors in the brain

Acetylcholine

Dementia and Alzheimer´s disease

senile dementia – slowly progressive loss of intellectual

ability (5 % over the age of 65, 20% over 80)

Alzheimer´s disease – same pathology irrespective of the

age of onset

selective loss of cholinergic neurons was found in dementia

to facilitate cholinergic transmision choline (precursor),

donepezil (AChE-I)

Acetylcholine

Parkinson´s disease, Huntington´s chorea

cholinergic neurons of the corpus striatum

ACh release from the striatum is strongly inhibited by D

hyperactivity of cholinergic neurons (associated with a

lack of D) hypokinesia, rigidity, tremor (Parkinson´s d.)

- M – antagonists

hypoactivity (associated with an excess of dopamine)

hyperkinetic movements, hypotonia (Huntington´s

chorea) - anticholinesterase

Dopamine

large amount corpus striatum (coordination of movement)

also in limbic system dopaminergic neurons lack dopamine -hydroxylase,

and thus do not produce NA

Receptors: D1, D5 - of AC; D2 , D3, D4 - of AC

Dopamine

Motor system

Deficiency of dopamine in nigrostriatal pathway

Parkinson´s disease (degenerative disorder - lack of dopamine)

parkinsonism (e.g. long term use of antipsychotic drugs - receptor blockade) rigidity tremor hypokinesia

Dopamine

Behavioral effects schizophrenia in man is associated with

dopaminergic hyperactivity

Anterior pituitary gland dopamine and dopamine receptor agonists

of prolactin secretion dopamine increases growth hormone secretion

paradoxically, dopamine agonists the

excessive secretion responsible for acromegaly (bromocriptine)

Dopamine

Vomiting

D2- receptors (in chemoreceptor trigger zone)

important role in nausea and vomiting

drugs that dopamine release in the brain nausea

and vomiting

D-antagonists (phenotiazines, metoclopramide) anti-

emetic activity

Serotonin (5-HT)

distribution of 5-HT neurons is very similar to that of NA neurons Receptors: 5-HT1A-F, 5-HT2A-C, 5-HT3, 5-HT4, 5-HT5A-B, 5-HT6,

5-HT7

Sleep, mood depletion of 5-HT Insomnia 5-HT, as well as NA, may be involved in the control of mood

deficit depression

Hallucinatory effects many centrally acting 5-HT antagonists are hallucinogens (LSD) 5-HT neurons inhibitory influence on cortical neurons loss of

cortical inhibition (e.g. by LSD) hallucinogenic efect

Serotonin

Sensory transmission depletion of 5-HT exagerated responses to many

forms of sensory stimuly

5-HT exerts an inhibitory effect on pain transmission

synergistic effect between 5-HT and opioid analgesics

depletion of 5-HT antagonises the analgetic effect

of opioids

Serotonin

Autonomic and endocrine function temperature regulation control of BP control of sexual function

Clinical implications depression, anxiety migraine, emesis

GABA

mainly in the nigrostratial system principal inhibitory transmitter in the brain

Receptors GABA-A – part of Cl- channels (BZD, barbiturates, alcohol) GABA-B - presynaptic, G-protein linked - inhibition of

transmitter release

Clinical implications Insomnia, anxiety alcohol withdrawal Spasticity, epilepsy

EXCITATORY AMINO ACIDS (EAA)

particularly glutamate and aspartate

Receptors: AMPA, Kainate receptors

rapid neurotransmission

NMDA long-term potentiation excitotoxicity pathogenesis of epilepsy

Functional aspects of NMDA receptors

long-term potentiation enhancement of synaptic transmission (days or week) in

various CNS synapses after short stimulation (learning, memory)

excitotoxicity entry of Ca2+ produced by NMDA receptor activation

neuronal damage following cerebral ischemia

pathogenesis of epilepsy ??? - high concentration of glutamate in areas

surrounding an epileptic focus

Antipsychotic drugs

Features of psychosis

Delusions

HallucinationsGrossly disorganized speech or behavior

Uses of antipsychotic drugs

SchizophreniaManic phase of Bipolar DisorderMajor depression with psychotic featuresothers

Characteristics of schizophrenia

Chronic psychotic illness characterized by disordered thinking and a reduced ability to comprehend reality.

Prevalence 0.5–1.0% of population

Onset Positive features in late adolescence or early adulthood Aspects of cognitive deficits detectable earlier in life

Comorbidity Depression: 30–50%∼ Substance abuse: 50%∼ Suicide: 5–10%∼

Schizophrenia - symptoms

Positive Symptomsdelusionshallucinations thouhgt disorder

Negative Symptoms low motivation, social involvementemotional abnormalitiescognitive deficits = attention, planning, memory language problems

Schizophrenia - a disease with various aspects

Positive SymptomsDelusions

HallucinationsDisorganized speech

Ca

Negative SymptomsAffective flattening

AnhedoniaSocial withdrawal

Cognitive DeficitsAttentionMemory

Executive functions(e.g., abstraction)

Mood SymptomsDepression

AnxietyAggression

HopelessnessSuicidality

Social/OccupationalDysfunction

WorkInterpersonal relationship

sSelf-care

Simplify neurocircuitry of dopamine in schizophrenia

Negative symptoms

DA

Mesolimbic pathwayHyperdopaminergia

D2

Positive symptoms

DA

Mesocortical pathwayHypodopaminergia

D1Limbic PFCx

The cause of schizophrenia

Etiology is unknown..... but...

combination of genetic and environmental factors

associated with neurodevelopmental disorder

affects several brain areas

Dopamine theory

Dopamine theory Schizophrenia is caused by excess dopaminergic activityArose in 1950s - 1960s: First effective antipsychotic drugs = dopamine antagonists

Other supporting evidence: Reserpine = “dopamine depleter” has some weak antipsychotic activity DA enhancers (anti-Parkinson drugs, amphetamine) mimic some positive symptoms: hallucinations, delusions apomorphine bromocriptine potent D2-receptor agonists - produce similar effects exacerbate the symptoms in schizophrenic patients

Dopamine theory: contrary evidence

D2 antagonists are not specific for schizophrenia reduce psychosis in other conditions, too

Growing appreciation of other neurotransmitter systems

Glutamate 5-HT Others: ACh, GABA

Lot of CSF, urine, serum, postmortem, imaging, functional studies have not yielded consistent support for a primary DA changes in untreated patients

Dopamine, still Important

Is schizophrenia caused by DA defect ??????

But antipsychotic drugs do act via DA systemWhich receptors?What brain regions?Role in side effects?

Dopamine receptor subtypes

D1 - D5

D2 mediates much of ‘typical APD’ therapeutic action . . .

. . . and side effects

Dopamine pathways in the brain

11

22

33

44

Mesolimbic dopamine system

DA worsens delusions, hallucinationsD2 blockade alleviates delusions, hallucinations

Mesocortical dopamine system

DA motivation, reward, other ‘higher functions’D2 blockade worsens ‘negative symptoms’

Nigrostriatal dopamine system

DA Essential for extrapyramidal motor functionD2 blockade produces extrapyramidal symptoms

Tuberoinfundibular dopamine system

DA inhibits prolactin release D2 blockade hyperprolactinemia

Antipsychotic drugs

Effective with regard to positive

symptoms in 20-30% of patients

Much weaker effect on negative

symptoms than positive symptoms

Significant parkinsonian symptoms and

anticholinergic effects (poor

compliance and potentially disabling)

Tardive dyskinesia in a minimum of

20% of patients who receive chronic

neuroleptic treatment.

At least as effective as typical

neuroleptics with regard to positive

symptoms

More effective than typical agents with

regard to negative symptoms

Much lower incidence of parkinsonian

symptoms and anticholinergic effects

than typical agents

TD does occur but at much lower

incidence

Elevated risk of metabolic side effects

Typical antipsychotics

Chemical classes:Phenothiazines - chlorpromazine, fluphenazineThioxanthenes - thiothixineButyrophenones - haloperidol, droperidolOther: loxapine (dibenzoxazepine), molindoneDiphenylbutylpiperidines: pimozide

Typical antipsychotic drug actions

D2 Dopamine antagonism

Muscarinic receptor antagonism

1 adrenergic receptor antagonism

Histamine H1 receptor antagonism

D2 receptor blockade

Therapeutic effects Amelioration of the positive signs, symptoms of

psychosis, manic symptoms, aggressive behaviors

Antiemetic effect

D2 receptor blockade

Adverse effects Extrapyramidal symptom (EPS)

Acute; akathisia, acute dystonia, parkinsonism

Late; tardive dyskinesia

Endocrine effects: prolactin elevation

Weight gain due to increase feeding

Spectrum of EPSL

ate

on

set

Acu

te

on

set

Acute dystonia

Tardive Dystonia vs. Tardive Dyskinesia

Tardive dystonia• Strikes younger• Strikes sooner in the

course of neuroleptic treatment

• Poor prognosis• More males• Patients with mood

disorders may be more susceptible

• Anticholinergics may improve condition

Tardive dyskinesia• Strikes older• Strikes later in the course

of neuroleptic treatment• Variable prognosis• More females (?)• Patients with mood

disorders may be more susceptible

• Anticholinergics usually worsen condition

Neuroleptic malignant syndrome

NMS is an uncommon but serious and potentially fatal complication of therapy

It is a syndrome of EPS, hyperthermia, altered consciousness, and autonomic changes (tachycardia, unstable BP, incontinence)

Management Discontinuation of the antipsychotic agents Supportive therapy Bromocriptine may be benificial

The onset is sudden and recovery may take 5-10 days after discontinuation of the agent

Spectrum-based concept of NMS

Anticholonergics Lorazepam Lorazepam Lorazepam

Bromocriptine

Amantadine

Dantrolene

Bromocriptine

Amantadine

Hyperprolactinemia

J Clin Psychopharmacol 2007;27:639–661.

Osteoporosis

M receptor blockade

Possible therapeutic effect Anticholinergic activity also has a beneficial effect:

Counteracts Parkinsonian side effects of antipsychotic drugs

Adverse effects All typical APDs have some muscarinic receptor

antagonism Constipation Urinary retention Exacerbation of narrow angle glaucoma Sinus tachycardia Blurred vision

Antimuscarinic activity varies greatly among antipsychotic drugs

1 receptor blockade

Adverse reactions All typical APDs have some 1 adrenergic receptor

antagonism Orthostatic hypotension Acute high doses (e.g. psychiatric emergencies) may produce

cardiovascular collapse, death

Anti- 1 activity varies greatly among antipsychotic drugs

Histamine H1 receptor blockade

Adverse reactions Somnolence - can be profound Weight gain

Antihistamine activity varies greatly among antipsychotic drugs

High-potency vs. Low-potency APDs

Antipsychotic drug spectrum:

High-potency: e.g. HaloperidolHigh: EPSLow: antimuscarinic, hypotension, sedation

Low-potency: e.g. ChlorpromazineLow: EPSHigh: antimuscarinic, hypotension, sedation

Spectrum of Adverse Effects Caused by Antipsychotic Drugs

Low PotencyFewer extrapyramidal reactions

(especially thioridazine)More sedation, more postural

hypotensionGreater effect on the seizure

threshold, electrocardiogram (especially thioridazine)

More likely skin pigmentation and photosensitivity

Occasional cases of cholestatic jaundice

Rare cases of agranulocytosis

High PotencyMore frequent extrapyramidal

reactions

Less sedation, less postural hypotension

Less effect on the seizure threshold, less cardiovascular toxicity

Fewer anticholinergic effects

Occasional cases of neuroleptic malignant syndrome

Typical (old fashioned) antipsychotic drugs

‘Typical APD’s - 1950’s to presentstill used due to low cost & in special situationsprimarily treat positive symptoms imperfect:

fail to help many patients’ positive symptoms tend to make negative symptoms worse have many side effects

Despite their problems, they revolutionized treatment of this devastating illness

Atypical Antipsychotic Agents: Mechanism

D2 receptor antagonism

5-HT2A serotonin receptor antagonism

May also involve other actions: most of the atypicals also have substantial affinity for other DA, 5-

HT, adrenergic receptors

DA

D1D2

Caudate/putamen

Normal function

Sunstantia nigra pars

compacta

5-HT2A

-

5-HT

Raphe

Role of 5-HT in Nigrostriatal Dopaminergic Synapse

Nigrostriatal tract

DA

D1D2

Caudate/putamen

EPS

5-HT2A

-

5-HT

Raphe

Role of 5-HT in Nigrostriatal Dopaminergic Synapse

Nigrostriatal tract

Typical

Sunstantia nigra pars

compacta

DA

D1D2

Caudate/putamen

Less EPS

5-HT2A

-

5-HT

Raphe

Role of 5-HT in Nigrostriatal Dopaminergic Synapse

Nigrostriatal tract

Atypical

Sunstantia nigra pars

compacta

What defines ATYPICAL antipsychotics?

Atypical APD’s have some of the following:

Positive sympt.: increased therapeutic efficacy i.e. in treatment resistant patients

Negative sympt : some therapeutic efficacy motivation, social withdrawl, cognition

Side effects: generally less than typical drugs Acute EPS: Parkinsonian, Dyskinesias, Akathisia Chronic EPS: Tardive Dyskinesia Endocrine: Hyperprolactinemia

Side Effects of Typical vs. Atypical Neuroleptics

“Typical” “Atypical”

EPS +/++++ 0/+

Akathisia +/++++ 0/+

Cognitive problems +++ 0/++

NMS + 0/+

Tardive dyskinesia +++ +/++

Hyperprolactinemia +++ 0/++

Side-Effects

Extrapyramidal side effects (EPS): Risperidone > Olanzapine = Ziprasidone > Quetiapine >

Aripiprazole ?=? Clozapine

Anticholinergic: Clozapine > Olanzapine > others

Hypotension: Clozapine > > Quetiapine, Risperidone > Ziprasidone, Olanzapine,

Aripiprazole

Side-Effects

Sedation Clozapine > > Olanzapine, Quetiapine > Risperidone, Ziprasidone,

Aripiprazole

Prolactin elevation Risperidone > others

Weight gain Clozapine = Olanzapine > Quetiapine, Risperidone > Ziprasidone,

Aripiprazole

Agranulocytosis: Clozapine

Metabolic effects

Weight gain over 1 year (kg)

aripiprazole 1

amisulpride 1.5

quetiapine 2 – 3

risperidone 2 – 3

olanzapine > 6

clozapine > 6

Clozapine

Few EPS, no TD, no elevated prolactin

Can cause life threatening Agranulocytosis and risk of seizures at higher doses

Is sedating and causes weight gain

Greatest efficacy, but highest side effects of atypical antidepressants

Side Effects of Clozapine

Highly anticholinergicStrong 1 blocker

Agranulocytosis - loss of granulocytesAs common as 1-2%Usually occurs in first 6 months of therapyOften fatal (to 35%)Adds significantly to financial cost of therapy - $10k/yr

MyocarditisAs common as 0.2%Occurs mostly in first month of therapy

Risperidone

Good at low doses, but mimics conventional neuroleptics at higher doses

Used with elderly, children and adolescents due to low dose needs

Elevates prolactin

May improve cognitive functioning in Alzheimer’s and may improve mood in schizophrenia, manic and depressive phases of bipolar

Does not block histamine H1 receptors less weight gain

Olanzapine

Usually no EPS- even at high dosesSo used with more severe cases

Improved mood in bipolar and improved cog. functioning in schizophrenia and dementia

Weight gain, moderate sedation, low prolactin, low TD

Expensive

Quetiapine

Virtually no EPS at any dose, no ProlactinThus good for patients with Parkinson’s and Psychosis

Weight gain, may cause cataracts (animal studies)

Mood and cog func. Bipolar, Dementia, Schizophrenia

Ziprasidone

Low EPS, low prolactin

No weight gain

Antidepressant and anxiolytic properties due to additional inhibition of 5HT and NE reuptake

Cog. and Mood: Bipolar, schizophrenia, Dementia

Past Areas of Concern

Current Medical Realities

Shift in Risk Perception of Antipsychotics

SedationWeight Gain

Insulin Resistance

CHD

Hyper-lipidemia

Weight Gain

Diabetes

Prolactin

Insulin Resistance

Sedation

Hyperlipidemia

Coronary HeartDisease

Tardive Dyskinesia

TD

Prolactin