Antipsychotic agents

----Schizophrenia ( 精神分裂症 ), is a particular kind of psychosis characterized by a clear sensorium but a marked thinking disturbance

Case Study

• W.G, 19 years old, undergraduate, member of rowing team of school, was found staying by himself, avoiding the company of friends and skipping school and athletic training. Later, he was heard speaking to himself as he sat isolated in his room, mumbling and smiling. Then he confided to his roommate that he had uncovered a grand conspiracy to rob him of his athletic abilities and that he could hear the conspirator’s voices as they planed to destroy him. Finally, he accused his roommate of being a part of the conspiracy.

EpidemiologyEpidemiology

•Incidence consistent worldwide --1% general population--10% siblings , parents / offspring, dizygotic twins--50% monozygootic twins

•Environmental factors implicated--Prenatal stress - infection, famine, war, death of spouse--Season of birth - winter > summer--Urban setting > rural setting

•Age of onset--Men 17 - 27, Women 17 - 37--Childhood onset extremely rare: 1 in 10,000-100,000

•Outcome--10% good - optimistic--80% remission(缓和） without full recovery--10% no remission

Signs & SymptomsSigns & Symptoms1. Positive symptoms

• Delusions ( 错觉 )- fixed false beliefs outside cultural norm (bizarre vs. non bizarre)

• Hallucinations ( 幻觉 )- perceptual (hearing), have no outside source

•“Like my voice”• Not an illusion ( 幻想， a mistaken perception for which there is an actual external stimulus)

• Disorganization – pattern of speech/thought/behavior, making up words without a meaning (neologisms)

2. Negative symptoms• Affective flattening (absence of emotional

expressiveness)• Avoliition/Amotivation (decreased motivation)• Autistic behaviors (social withdrawal)• Anhedoonia (inability to experience pleasure )• Ambiivalence (coexistence of opposing attitudes or

feelings) • Anosognoosia (impaired awareness of illness )

Signs & SymptomsSigns & Symptoms

Historical Perspective• Chlorpromazine ( 氯丙嗪 ) made in 1950 in France, used

to treat pre-operative anxiety• 1952 Delay and Deniker published the first report of

Chlorpromazine's efficacy in psychosis• 1963 Carlsson and Lindquist report that Haloperidol and

Chlorpromazine result in accumulation of DA metabolites

• D2 hypothesis (excessive dopaminergic activity plays a role in the disorder) - 1976 Seeman et. al. and Creese

et. al. report that “potency” of DA antagonism at D2 related to efficacy

• Refs: http://www.bedrugfree.net/Schizophrenia.pdf

Film: One Flew Over the Cuckoo’s Nest (1975)

Classification of antipsychotics

Typical:

• Phenothiaazines ( 吩噻嗪类 ): chlorproomazine

• Thioxanthenes ( 硫杂蒽类 ): chlorprothixene

• Buutyrophenones ( 丁酰苯类 ): halopeeridol

Atypical:

• Clozapine （氯氮平） , olanzapine （奥氮平） , risperidone （利培酮）

Available Medications• Typical medications (D2 receptor antagonists)

– Low potency agents - Chlorpromazine (sedation)– High potency agents - Haloperidol (motor

problems – extrapyramidal effects)

• Atypical agents– Clozapine – 5-HT2 and D4 receptor antagonist, great

efficacy– Olanzapine （奥氮平）– 5-HT2, D1, D2, M, H, αreceptor

antagonist, good– Risperidone （利培酮）– 5-HT2 and D2 receptor

antagonist, good

Typical Antipsychotics

• Good ability to treat hallucinations and delusions in most people within approximately 2 months

• Limited effect on negative symptoms– Flat affect– Avolition– Anhedonia– Alogia– Attentional impairment (Cognition)

Dopaminergic pathways in CNS and drugs for schizophrenia

A. mesolimbic and mesocortical pathways

related with psychological activities and the therapeutic effects of drugs.

B. nigrostriatal pathway

related with extrapyramidal adverse effects of drugs

C. Tuberohypoophyseal pathway

related with hypothalamus endocrine adverse effects of drugs

a) Antipsychotic effects (neuroleptic effects)

-- controls excitation and then hallucinations (slow, weeks to months)

b) Antiemetic effects

-- inhibits chemoreceptor trigger zone (CTZ) in the medulla

Chlorpromazine

1. 1. Pharmacological effectsPharmacological effects

(1) Central effects(1) Central effects

c) Poikilothermic effects (comparison with NSAIDs)

-- hypothermic anesthesia

-- artificial hibernation (with mepeeridine 哌替啶 , promethazine 异丙嗪 )

d) Extrapyramidal effects (nigrostriatal pathway blockade)

-- primary adverse effects

e) Potentiating the effects of central depressants

-- sedative-hypnotics, analgesics, general anesthetics, ethanol

Chlorpromazine

(2) Effects on autonomic nervous system

a) Hypotensive effects receptor blockade, postural hypotension

b) Anticholinergic effects

dry mouth, constipation, blurred vision, urinary retention, increased intraocular pressure, etc.

Chlorpromazine

(3) Endocrine effects (Tuberohypoophyseal pathway blockade)

Prolactin Estrogen, progestin, ACTH, growth hormone

Chlorpromazine

2. Clinical uses

(1) Treatment and prevention of acute schizophrenia and mania

(2) Treatment of emesis and hiccough but ineffective on motion sickness

(3) Hypothermic anesthesia and artificial hibernation

combined with lowering room temperature

Chlorpromazine

3. Side effects• Motor - proportional to D2 blockade of nigrostriatal pathway

– EPS (extrapyramidal syndrome) - misnomer, stiffness,

tremor (parkinsonism), akathiisia (inability to sit still ),

acute dystonia (twisting and repetitive movements or

abnormal postures)

Chlorpromazine

• TD (tardive dyskinnesia)- licking, sucking, chewing (twitching of the muscles around the mouth), described before meds existed, exacerbated in some, may be irreversible

3. Side effects• NMS (neuroleptic malignant syndrome, induced by

excessive blocking of DAergic system): high fever, hypertension, tonus, autonomic system disorder, even death.

Chlorpromazine

Treatment: DA agonists (eg bromocriptine), DA releasers (eg amantadine), and muscular relaxants (eg scoline)

3. Side effects• Sedation• Cardiac - lengthen QT interval• Seizures• Endocrine - prolactin elevations• Drooling （流涎）• Weight gain

Chlorpromazine

Haloperidol 氟哌啶醇• High efficacy for positive symptoms• Weaker sedative effect• Weaker and M receptor antagonism• More severe EPS• Also can be used for anxiety, hiccup, vomiting• Terotogenicity (Class C, should be given only if

the potential benefit justifies the potential risk to the fetus)

Then came clozapine( 氯氮平 )

• Worked better than the rest (on some patients)

• Relatively weak binding at dopamine D2 receptor

• Better efficacy at lower D2 receptor occupancy

• Relatively stronger binding at serotonin receptors• “Dirty” drug - acts at many different types of

receptors (D4, D2, 5-HT2)

Other atypical antipsychotics: olanzapine( 奥氮平 ), loxapine( 洛沙平 ), risperidone( 利培酮 ), aripirazole( 阿立

哌唑 ), etc.

“Atypical” Antipsychotics

Many definitions:• Work better on positive symptoms ? - No• Work for “negative symptoms” ? – Some• Better cognitive effect- No• Less hormonal side effects ? - Prolactin -

Sometimes• More easily tolerated? - equivocal, likely dose

dependent• Less motor side effects ? - Yes

Case study --continued

W.G. was taken to see a psychiatrist. He was diagnosed schizophrenia and hospitalized. Haloperidol was started at a dose of 10 mg/d. On the second day, he was found to develop a “seizure”. His neck was strained backward with his face turned upward toward the ceiling. He was having difficulty speaking but was quite conscious of his surroundings. The attending physician recognized this as an acute dystonia and ordered an immediate injection of benztropine. Haloperidol was replaced with loxapine accompanied with benztropine. 3 weeks later, his delusions and hallucinations disappeared and he developed insight into his problems. One month later, he left the hospital and resumed his academic life.

Compliance with Medication• Studies show that 50% of all people do not

consistently take medications as prescribed - all illnesses.

• Some studies have found as few as 20% of people take antipsychotics as recommended.

• Severe consequences to stopping medication

• Most significant advances on the horizon are likely going to involve improved compliance interventions

Antidepressant Agents

Depression ( 抑郁症 ) is a kind of mood disorders (mania,

depression, anxiety) with symptoms such as intense

feelings of sadness, hopelessness, despair, and inability to

experience pleasure in usual activity.

Lecture Outline

• Depression

• Neurotransmitter systems associated with the disease and the treatment

• Classifications of antidepressant drugs

- chemical structure

- efficacy, side effects, toxicity

- mechanism of action

• Other therapy for depression

Leading Sources of Disease Burden*

• Ischemic Heart Disease• Unipolar Major Depression• Cardiovascular Disease• Alcohol Use• Traffic Accidents• Lung and other cancers• Dementia and Neurodegenerative Disorders

*based on DALY’s (Disability Adjusted Life Years, WHO) which measure lost years of healthy life due to premature death or disability

Criteria for Diagnosis of Major Depression

• Depressed Mood

• Loss of interest or pleasure in almost all activities

• Significant weight loss or gain or change in appetite nearly every day

• Insomnia or hypersomnia

• Psychomotor agitation or retardation

• Fatigue or loss of energy

• Feelings of worthlessness or inappropriate guilt

• Diminished ability to think or concentrate; indecisiveness

• Recurrent thoughts of or attempts at suicide; wishing one were dead

At least 2 weeks of ≥5 of the above features, which are present most of the day or nearly every day; must include depressed mood or loss of interest or pleasure.

Monoamine Hypothesis of Depression

• Functional deficiency of Norepinephrine (NE) or Serotonin (5-Hydroxytryptamine, 5-HT) in the brain is key to the pathology and behavioral manifestations associated with depression.

中缝核

兰斑核

Classifications of Antidepressants

• Tricyclic Antidepressants (TCAs ，三环类抗抑郁药 )

and heterocyclics

• Selective Serotonin Reuptake Inhibitors (SSRIs)

• Selective Norepinephrine Reuptake Inhibitors (NRIs)

• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs)

• Monoamine Oxidase Inhibitors (MAOIs)

• Norepinephrin-Serotonin Releasers

地昔帕明

TCA’s are highly related in their chemical structures

丙咪嗪 阿米替林

去甲替林

氯丙咪嗪

Doxepin 多塞平

NRIs

TCAs

Mechanisms: Non-selective monoamines (mainly

NE and 5-HT) reuptake inhibitors

Clinical uses: depression, anxiety, obsessive

compulsive disorder, panic disorder, neuropathic

pain, enureesis

Side effects

Toxicity - Narrow dose response range. Normal plasma levels 0.1-0.2 mg/mlToxic effects are seen at 1.0 mg/ml

Anticholinergic - dry mouth, constipation, dizziness, blurred vision, tachycardia, urinary retentionHypotension and Sedation - due to adrenergic blocking properties and/or anti-histaminergic

Selective norepinephrine reuptake inhibitors

尼索西汀 托莫西汀 瑞波西汀

地昔帕明 去甲替林 Amoxapine 阿莫沙平

For severe depression

氟西汀，百忧解 舍曲林 帕罗西汀

氟伏沙明 西酞普兰茚达品

Selective serotonin reuptake inhibitors: used for both anxiety and depression

Side effects

• GI upset, weight gain and low libido• Serotonin Syndrome:

- Occurs when switching among SSRIs or to other drug classes

- Potential for over-activation of central serotonin receptors

- Features: abdominal pain, diarrhea, sweating, fever, tachycardia, increased blood pressure, tremor and altered mental state, or even coma and death

Fluvoxamine taker (Luvox)

Eric Harris Dylan Klebold

Columbine High School massacre

Bupropion

• Glaxo Wellcome product

• Inhibits NE, DA and serotonin reuptake

• No weight gain or sexual dysfunction

安非他酮

Norepinephrine-dopamine reuptake inhibitors

文拉法辛

Serotonin-norepinephrine reuptake inhibitors

度洛西汀

Used for depression and generalized anxiety disorder obsessive compulsive disorder panic attacks neuropathic pain (duloxetine)Adverse effects: GI upset, headache, insomnia

Side effects: few anticholinergic, adrenergic side effectsbut toxicity associated with dietary interactions (tyramine)

MAO:---Regulates free intraneuronal concentration of NE or 5-HT---Regulates inactivation of endogenous and ingested amines

Monoamine Oxidase Inhibitors (MAOIs)

司来吉兰

吗氯贝胺

MAOIs and Dietary Interactions

• Tyramine is normally metabolized by MAO• Tyramine is sympathomimetic (it acutely

displaces NE from terminals to activate receptors)

• Ingesting tyramine during MAO inhibition results in hypertension, headache, palpitations, nausea, vomiting

• Tyramine is present in a number of foodstuffs, such as aged cheese, red wine, etc.

Norepinephrin-serotonin releaser

- Mirtazapine ( 米氮平 )

- Blocks presynaptic 2 receptor

- Promotes the release of NA and 5-HT

- Weight gain and postural hypotension are main adverse effects

Clinical Pharmacology of Antidepressants

• Depression: antidepressants, lithium• Panic disorder: benzodiazepine, SSRIs, MAOIs• Obsessive-compulsive disorders: selective and

mixed serotonin reuptake inhibitors• Enureesis: tricyclics• Neuropathic pain: tricyclics, norepinephrine

reuptake inhibitors

Individualized therapy

• Drug choice• Dosages: from small doses• Maintenance treatment: 6-8months after

remission, gradually withdraw• Monitoring plasma concentrations• Unresponsive patients: diagnosis, drug,

dose, duration of treatment (6-8wks), and different treatments

Alternative Treatments for Depression

• Herbal Therapy- St. Johns wort (Hypericum perforatum)

• Electroconvulsive Therapy

• Transcranial Magnetic Stimulation

• Exercise

Herbal TherapySt. Johns wort(Hypericum perforatum)

• Used extensively in Europe for mild to moderate depression

• British Study - found St. John’s Wort as effective as Paxil (Paroxetine)

• NIH - 3year study found no significant antidepressant effect

Electroconvulsive Therapy

• Brief electrical pulse to the scalp under anesthesia

• Neurons are excited causing them to fire in unison and produce a seizure

• Mechanism of effectiveness is unknown

Electroconvulsive Therapy

• 1930s: used for numerous psychiatric illnesses• 1970s: improved treatment delivery, increased

safety and comfort resulted in increased use• Most effective in severe depression and

medication response failure• Treatments are administered 3X week for a

course of 6-12 treatments total• Effects can be seen more rapidly (1-2 weeks)

than typical pharmacotherapy (3-6 weeks)

Transcranial Magnetic Stimulation

• Safe and noninvasive means of getting electrical energy into brain

• Procedure involves discharge of a large current (5000 amps) through a copper-wire coil

• Magnetic field produces currents in the induced electrical field lying parallel to the plane of the coil

• Currents can excite axons lying in the plane of the induced field in a manner similar to that achieved with direct cortical stimulation with electrodes

Transcranial Magnetic Stimulation

• Repetitive TMS (rTMS) • Similar to ECT but less

intense and given over specific areas of the brain for a longer time than ECT

• No anesthesia or seizure production

Exercise

Exercise as an augmenting Treatment for major Depressive Disorder: A Pilot Study

Friedman. R., et al, Society for Neuroscience 2003 Abstract 851.9

*treadmill, walking or cycling for 12 weeks, 30 min for most days of the week

- Lithium carbonate

- Antiphsychotics

- Antiepileptics

- Calcium channel blockers

AppendixDrugs for mania

Lithium carbonateLithium carbonate

• Lithium is an anti-mania drug with narrow TI;

• Start with small dosage. Dosage regimens should be individually titrated to desired concentrations and clinical response of the patients;

• The toxicity should be monitored regularly;

• The patients and/or their families should be educated.

AppendixDrugs for mania

Therapeutic range of lithium

Disease or conditionDisease or condition

Acute mania

Prophylaxis of mania and/or depression

Therapeutic rangeTherapeutic range

0.5-1.2 mmol/L

0.6-0.8 mmol/L

1.2-1.5 mmol/L may be required in selected patients

Concentration-related toxicity of lithiumConcentration-related toxicity of lithium

Potential side effects under therapeutic concentrations: Agitation, cog-wheel rigidity, confusion, delirium, dysarthria, increased deep tendon reflexes, memory impairment, seizures.

Mild toxicity (>1.5 mmol/L): Fatigue, fine tremors of the limbs, gastrointestinal disturbances, muscle weakness

Moderate toxicity (1.5-2.5 mmol/L): Ataxia, coarse tremors, dysarthria, headaches, hyperthermia, impaired sensorium, increased deep tendon reflexes, lethargy, nystagmus, sedation

Severe toxicity (>2.5 mmol/L): Basal ganglia dysfunction, coarse tremors, delirium, respiratory complication, seizures, death

Pharmacological Treatment of

Parkinson’s Disease Parkinson’s disease, one of movement disorders, is a degenerative

disease of the brain that often impairs motor skills, speech, and

other functions

Parkinson’s Parkinson’s disease (PD)disease (PD)

Parkinsonism: -Muscle rigidity

-Tremor

-Bradykinenesia

(slowness of

motion), or even

akinesia (loss of

motor function)

-Postural instability

(propulsion,

retropulsion).

Tremor of one hand

Dopaminergic neuronal loss in the substantia nigra

Substantia nigra Substantia nigra

(striatum)

Dopamine

Acetylcholine

Imbalance of DA/ACh neuronal functions in extrapyramidal system of Parkinson’s disease

Different approaches including:

I Increases in dopamine synthesis capacity (L-DOPA)

II Direct activation of post-synaptic receptors

III Inhibition of dopamine metabolism (MAOIs)

IV Alteration of the interaction/balance with other

neurotransmitters (Ach)

V Dopamine releasers

VI L-DOPA metabolism inhibitors (adjuvant)

How to reach the desired goal of pharmacological therapies for Parkinson’s

disease?

Note: All therapies treat the symptoms of the disease; none is neuroprotective and none slows the progression of the disease

NH2

OH

OH

O

OH

OH

OH

NH2

Dopamine

L-DOPA decarboxylase

L-Dopa

B6

Rationale for L-DOPA Precursor Loading:

• Striatal dopamine levels are low in PD. • Dopamine does not pass BBB and, hence, has no therapeutic effect in PD. • L-DOPA , an amino acid, the immediate

precursor to dopamine, is transported across BBB.

How to increase dopamine synthesis capacity? Provide DA precursor: L-DOPA (Levodopa )

(AAAD)

What happens to L-DOPA in the periphery?

L-DOPA peripheral metabolism

How to reduce peripheral metabolism of L-DOPA? - peripheral decarboxylase inhibitor

Carbidopa, a peripheral decarboxylase (AAAD) inhibitor, increases L-DOPA bioavailability; and decreases its adverse effects by allowing lower L-DOPA dosages to be used.

dopamine

Periphery CNS

L-DOPA

BBB

L-DOPA

dopamine

AAADAAAD

Peripheral adverse effects Therapeutic effects

－

＋

Carbidopa

息宁

Early -

• Gastrointestinal effect: nausea or vomiting

• Cardiovascular effect: tachycardia,

hypertension, orthostatic hypotension

• Emotional depression/ psychosis (clozapine)

What are the major adverse effects of L-DOPA?

Late –

• Fluctuation of response: end-of-dose/“wearing off” periods; on/off periods (sudden loss of symptom control, akineesia alternates improved mobility).

• Dyskinesia (months to years after, up to 80%, increase of involuntary movements: chorea, balliismus, athetosis, dystonia, myooclonus, tics, and tremor, any part of the body may be involved).

What are the major adverse effects of L-DOPA?

• Reduces metabolism of L-DOPA in the periphery but not the CNS

• Used as adjuvant with Sinemet (note: only effective when combined

with L-DOPA)

• May reduce “on-off” fluctuations and dyskinesias

How to reduce peripheral metabolism of L-DOPA?-- peripheral COMT inhibition

HO

HO

O2N

C CC

CN

N

OH

Entacapone

dopamine

Periphery CNS

L-DOPA

BBB

L-DOPA

dopamine

AAADAAAD

Peripheral adverse effects Therapeutic effects

－

＋

Carbidopa

息宁

3-OMD

Entacapone

1st generation agonists: (ergot derivatives)

bromocriptine* (D2 agonist) (t1/2 ~ 12 h)

pergolide* (D2/D3 agonist)(t1/2 ~ 24 h)

溴麦角环肽和培高利特2nd generation agonists: ropinirole (t1/2 ~ 6 h) (D2/D3 agonist)

pramipexole (D2 agonist) (t1/2 ~ 8 -12 h)

罗平尼咯和普拉克索Can be used as monotherapy for mild parkinsonism, or combined with levodopa for advanced disease, permitting the dose of levodopa to be reduced and smoothing out response fluctuations and dyskinesias.

II. How to activate post-synaptic DA receptors? - Dopamine receptor agonists

NO

H

N

Ropinrole

N

SH2N

N

HPramipexole

Bromocriptine

Ergot Alkaloids (background)

 

-isolated from the fungus Claviceps purpurea found on rye and wheat and other grains.

-ergotism can cause nausea, and mild symptoms: diarrheasevere symptoms: hallucinations, delirium and seizures

- main sites of action: 5-HT receptors, dopamine receptors and alpha 1 adrenergic receptors

- causes uterine contraction, vasoconstriction, dopamine receptor agonist activity

麦角生物碱类

• Dyskinesia and response fluctuation (lower incidence)

• Some individuals develop a troubling sleep disorder, with

sudden attacks of sleep ( 突然昏睡 ) during ordinary daytime

activities (the second generation agonists)

• Postural hypotension

• Dose-related psychiatric side effects (similar to L-DOPA

but may occur more frequently, especially in elderly)

• Nausea or vomiting (drugs active at chemotrigger zone

(CTZ) )

What are the major adverse effects of DA receptor agonists?

Dopamine Agonists

Apomorphine (Apokyn) 阿朴吗啡

- is a short-acting non-ergoline dopamine agonist (t1/2 ~ 40 min) at D1 and D2 receptors

-can provide rapid “rescue” within 4 - 8 min after injection for an undermedicated or “frozen” state; indicated for the acute, intermittent treatment of hypomobility, "end-of-dose/wearing off" and unpredictable "on/off" episodes associated with advanced Parkinson’s disease.

- morphine structural analog but lacks any analgesic actions or risk for causing dependence or addiction

III. How to inhibit dopamine metabolism? - Selective MAO-B inhibition

• MAO-B is the predominant form in the striatum and is responsible for

the oxidative metabolism of dopamine. • At low therapeutic concentrations, these drugs irreversibly inhibit MAO-

B selectively in the CNS • Peripheral metabolism of catecholamines (mostly through MAO-A) is

unaffected.• Drug interactions (potentiation) with SSRIs & TCAs (reuptake blockers)

(recall: MAO-A mostly outside brain; MAO-B > MAO-A in the brain)

N

CH

Selegiline Rasagiline

IV. How to alter the interaction/balance with other neurotransmitters (DA-ACh) ?

“Balance” Hypothesis of DA-ACh Striatal Interactions

Imbalance of dopamine and acetylcholine in Parkinson's disease.

Effects of Parkinson's disease therapy.

NCH2CH2COH

Trihexyphenidyl

NCH3

OCHC6H5

C6H5

Benztropine

• Weak efficacy (mostly for tremor)• Potential adverse effects:

• neuropsychiatric: sedation, poor concentration/memory, confusional state.

• blurred near vision due to mydriasis and cycloplegia. • dry mouth • constipation • urinary retention

Note: antihistamines (eg., diphenhydramine: H1-antagonist) also have muscarinic antagonist properties

Muscarinic Receptor Antagonists

Used for mild Parkinson’s disease, as an early monotherapy

• Mechanisms of action: release of dopamine, block DA reuptake, actions on glutamate receptors (as an NMDA-receptor antagonist)

• The dose should be reduced with renal impairment.

• Potential adverse effects:- CNS reactions (dizziness, anxiety, impaired coordination)- hyperkinesias- nausea, vomiting, etc

V. How to increase DA release? NH2

Amantadine

DRUG THERAPYReview

• Main Line Agents:• L-DOPA plus carbidopa (Sinemet®)• Dopamine receptor agonists (ropinirole)

• Lower Efficacy/Second Line or Adjuvant Agents:• Anticholinergics • Reuptake inhibitor or releaser (amantadine)• COMT inhibitor (entacapone)• MAO B inhibitors (rasagiline, selegiline)

• Reserpine, which depletes brain catecholamines, induces Parkinson’s disease symptoms

• Antipsychotics (neuroleptics), that block DA receptors, ie, dopamine receptor antagonists.

• N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) is a by-product of illicit synthesis of isomeperidine. MPTP first came to medical attention because it produced symptoms similar to Parkinson’s disease.

Drug-Induced Parkinsonism

Beyond Pharmacotherapy

Striatum - mesencephalic fetal cell transplantation - genetically engineered cells, infusion of growth factors - viral vector therapy (deliver genes for tyrosine

hydroxylase, and/or amino acid decarboxylase; neurotrophic factors

- stem cells Surgery

- radiofrequency lesion – pallidotomy- deep brain stimulation – subthalamic nucleus

Photograph showing an electrode being inserted during deep brain stimulation

Opioid analgesics (narcotic analgesics) and

antagonists

Collecting resin of opium poppy

Crude opium

Opium flowers

Seeds of opium poppy

• Natural opiates: morphine, codeine, papaverine and

thebaine;

• Semi-synthetic opiates: hydromorphone, hydrocodone,

oxycodone, oxymorphone, desomorphine,

diacetylmorphine (Heroin), nicomorphine,

dipropanoylmorphine, benzylmorphine and ethylmorphine;

• Fully synthetic opioids: fentanyl, pethidine, methadone,

tramadol and propoxyphene;

• Endogenous opioid peptides: endorphins, enkephalins,

dynorphins, and endomorphins.

1. Classification of opiates

2. Opioid receptors

2. Opioid receptors

2.1 Distribution and physiological effects:

A Certain cells in the CNS:

Brainstem: mediate respiration, cough, nausea and vomiting, maintain blood pressure, pupillary diameter and control of stomach secretions.

Medial thalamus: modulate deep pain that is poorly localized and emotionally influenced.

2.1 Distribution and physiological effects :

A Certain cells in the CNS:

Spinal cord: involved in the reception and integration of incoming sensory information and attenuate painful afferent stimulation.

Hypothalamus: affect neuroendocrine

secretion.

Limbic system: influence emotional behavior.

2. Opioid receptors

2.1 Distribution and physiological effects :

B Periphery:

--- Inhibit the release of excitatory,

proinflammatory substances from nerve endings, which contribute to the anti-inflammatory effect of opioids.

C Immune cells: immune depression

2. Opioid receptors

2.2 Signal transduction:

2. Opioid receptors

In the Spinal Cord

In the Brain Stem

2. Opioid receptors

Summary of opioid analgesics and antagonists:

Strong agonists: fentanyl, heroin, pethidine, methadone,

morphine

Moderate agonists: codeine

Mixed agonist-antagonists: pentazocine

Antagonists: naaloxone, naltrexone

3. Opioids

Mainly agonist action at μ receptors, but some actions on other receptors•Morphine•Heroin•Codeine•Fentanyl

⊕

Agonist action at κ receptors,with partial antagonist action at μ receptors•Pentazocine

⊕⊕

μ opioid receptor

κ opioid receptor

opioid receptor

AnalgesiaRespiratory depressionEuphoria/sedationPhysical dependenceDecreased GI motilityPupil constriction

AnalgesiaSedation/dysphoriaPupil constriction

Analgesia

Antagonist act at μ, κ, receptors•Naloxone•Naltrexone

low

highEfficacy

Addiction/abuse

Morphine Pethidine Methadone Fentanyl Codeine

A comparison of the maximum efficacy and addiction/abuse liability of commonly used

narcotic analgesics

20min4 hours

15min2 hours

5min45min

Morphine

Pethidine

Fentanyl

Time to peak effectDuration of action

Time to peak effect and duration of action of several opioids administered intravenously

4. Morphine

4.1 Pharmacological effects:

A Analgesia:

- Raises the pain threshold at the spinal cord level, alters nociception in the brain.

- Relieves anxiety and fear

解热镇痛药与阿片类镇痛药镇痛作用比较  阿片类镇痛药 解热镇痛药

作用部位 中枢 外周（主）

作用机制 激动阿片受体 抑制环氧酶，使 PG合成减少

镇痛特点 强大，伴有镇静作用及欣快感

中等强度，无镇静作用及欣快感

适应证 用其他药无效的急性锐痛 慢性钝痛

不良反应 易成瘾，抑制呼吸 无成瘾性及呼吸抑制

B Euphoria:

- Produces a powerful sense of contentment and well-being by stimulation of the ventral tegmentum 腹侧被盖 .

C Respiration:

- Causes respiration depression by reduction of the

sensitivity of respiratory center neurons to CO2.

D Depression of cough reflex:

- May allow accumulation of secretions and thus lead to airway obstruction and atelectasis ( 肺不张 ).

- Replaced by other safer antitussives .

4. Morphine

E Miosis:

- The pinpoint pupil is the characteristic of morphine use, little tolerance.

F Emesis:

- Causes vomiting by stimulating the CTZ in the medulla but with no unpleasant sensations.

4. Morphine

G Sedation:

- Causes drowsiness and clouding of mentation, even disrupting sleep

H Gastrointestinal effect:

- Decreases motility of smooth muscle and increases tone, which causes constipation and increases pressure in the biliary tract (worsens abdominal colic, eg. Sphincter oddi contraction).

4. Morphine

I Cardiovascular :

- Has no major effects on the cardiovascular system.

- Is usually contraindicated in individuals with severe brain injury (because that increased PCO2 induced by

respiration depression leads to cerebral vasodilation and consequential increase in cerebral blood flow and intracranial

pressure).

- Causes postural hypotension sometimes.

4. Morphine

J Histamine release:

- Causes pruritus 搔痒症 , urticaria 荨麻疹 , sweating, vasodilation and bronchoconstriction.

K Hormonal actions:

- Inhibits release of LH ( 黄体生成素 ).

- Increases GRH ( 促生长激素 ), ADH ( 抗利尿激素 ), PRL ( 催乳素 )

M Immune depression

4. Pharmacodynamics- morphine

4.2 Therapeutic uses: A Analgesia:

- Used for various pain, especially acute, obstinate constant pain (e.g. burn, cancer pain);

- Fixed interval of administration reduces tolerance and dependence;

- Severe pain of renal and biliary colic + MR blockers.

4. Morphine

B Cardiac asthma:

- Acute left ventricular heart failure induces pulmonary edema

- Reduces anxiety, cardiac preload and afterload.

- Particularly useful for painful myocardial ischemia with pulmonary edema.

C Treatment of diarrhea: synthetic surrogates （ eg. 地芬诺酯） .

4. Morphine

D Relief of cough: synthetic antitussives （ eg. 右美沙芬）

E Premeditate drugs before anesthesia : sedative, anxiolytic, and analgesic properties. For high-risk surgery administered systemically; for local (epidural) anesthesia.

Caution: respiratory suppression

4. Morphine

4.3 Adverse effects:

- Respiratory depression

- Vomiting, constipation, biliary colic

- Dysphoria

- Allergy-enhanced or postural hypotensive effects

- Urinary retention (prostatic hypertrophy)

- Elevation of intracranial pressure (head injury)

- Immune depression

4. Morphine

Tolerance and Physical Dependence

• Repeated use produces tolerance to the respiratory depression, analgesic, euphoric and sedative effects, but not to pupil-constricting and constipating effects.

• Physical and psychologic dependence readily occur for strong μagonists, especially used on necessities.

4. Morphine

Tolerance and Physical Dependence

• Withdrawal symptoms: a series of autonomic, motor and psychological response that incapacitate the individual (rhinorrhea, lacrimation, yawning, chills, gooseflesh, hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea, anxiety, and hostility).

4. Morphine

Druggy Malformation

4.4 Contraindications:

• Women during labor or lactation

• New-born infants

• Chronic obstructive pulmonary disease (COPD)

• Asthma

4. Morphine

5. Pethidine (meperidine)

5.1 Actions and mechanisms:

• Binds to opioid receptors, particularly receptor.

• Actions similar to but less potent than morphine.

----Transient decrease of gastro-intestinal motility and increase of the tone

---- Indistinctly central depression of cough reflex.

5. Pethidine (meperidine)

5.2 Therapeutic uses:

• Analgesia: various severe pain, including during obstetric labor (less depression of respiration in newborn infants)

• Cardiac asthma

• Administration before anesthesia and artificial hibernation, combined with chlorpromazine （氯丙嗪） and promethazine （异丙嗪）

6. Pentazocine

• An agonist on receptor, but a weak antagonist at and receptors (partial agonist).

• Actions (less potent than morphine): analgesia and respiratory depression, indistinct euphoria and dependence. Dysphoria, hallucinations and hypertension in high dose

• Used for moderate or chronic pain.

7. Naloxone

• Competitive blocker of opioid receptor, with ten-fold higher affinity for receptor than for .

• Actions:

--- precipitates withdrawal symptoms;

---reverses the coma and respiratory depression of opioid overdose (short action duration! Naltrexone with much longer action duration);

--- eliminates some adverse effects with opioids

8. Other analgesics

• Tramadol: weak receptor agonist, inhibits uptake of NA and 5-HT, effective on moderate to severe acute and chronic pain.

• Tetrahydropalmatine ( 延胡索乙素 ): effective on persistent blunt pain

Guidelines for neuropathic pain

WHO guidelines for cancer pain