Transcript Drugs That Act in the Central Nervous System

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.
Epidemiology
•
Incidence consistent worldwide
--1% general population
--10% siblings , parents / offspring, dizygotic twins
--50% monozygotic 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 & Symptoms
1. 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)
Signs & Symptoms
2. Negative symptoms
• Affective flattening (absence of emotional
expressiveness)
• Avolition/Amotivation (decreased motivation)
• Autistic behaviors (social withdrawal)
• Anhedonia (inability to experience pleasure )
• Ambivalence (coexistence of opposing attitudes or
feelings)
• Anosognosia (impaired awareness of illness )
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:
• Phenothiazines (吩噻嗪类): chlorpromazine
• Thioxanthenes (硫杂蒽类): chlorprothixene
• Butyrophenones (丁酰苯类): haloperidol
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. Tuberohypophyseal pathway
related with hypothalamus endocrine adverse
effects of drugs
Chlorpromazine
1. Pharmacological effects
(1) Central effects
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
c) Poikilothermic effects (comparison with NSAIDs)
-- hypothermic anesthesia
-- artificial hibernation (with meperidine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 (Tuberohypophyseal
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), akathisia (inability to sit still ),
acute dystonia (twisting and repetitive movements or
abnormal postures)
• TD (tardive dyskinesia)- licking,
sucking, chewing (twitching of the
muscles around the mouth), described
before meds existed, exacerbated in
some, may be irreversible
Chlorpromazine
3. Side effects
• NMS (neuroleptic malignant syndrome, induced by
excessive blocking of DAergic system): high fever,
hypertension, tonus, autonomic system disorder,
even death.
Treatment: DA agonists (eg bromocriptine),
DA releasers (eg amantadine),
and muscular relaxants (eg scoline)
Chlorpromazine
3. Side effects
•
•
•
•
•
•
Sedation
Cardiac - lengthen QT interval
Seizures
Endocrine - prolactin elevations
Drooling（流涎）
Weight gain
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
• Fatigue or loss of energy
• Loss of interest or pleasure
in almost all activities
• Feelings of worthlessness or
inappropriate guilt
• Significant weight loss or
gain or change in appetite
nearly every day
• Diminished ability to think or
concentrate; indecisiveness
• Insomnia or hypersomnia
• Psychomotor agitation or
retardation
• 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
TCA’s are highly related in their chemical structures
丙咪嗪
Doxepin 多塞平
氯丙咪嗪
阿米替林
去甲替林
地昔帕明
NRIs
TCAs
Mechanisms: Non-selective monoamines (mainly
NE and 5-HT) reuptake inhibitors
Clinical uses: depression, anxiety, obsessive
compulsive disorder, panic disorder, neuropathic
pain, enuresis
Side effects
Toxicity - Narrow dose response range. Normal
plasma levels 0.1-0.2 mg/ml
Toxic effects are seen at 1.0 mg/ml
Anticholinergic - dry mouth, constipation, dizziness,
blurred vision, tachycardia, urinary retention
Hypotension and Sedation - due to adrenergic
blocking properties and/or anti-histaminergic
Selective norepinephrine reuptake inhibitors
For severe depression
尼索西汀
地昔帕明
托莫西汀
去甲替林
瑞波西汀
Amoxapine 阿莫沙平
Selective serotonin reuptake inhibitors:
used for both anxiety and depression
氟西汀，百忧解
舍曲林
帕罗西汀
茚达品
氟伏沙明
西酞普兰
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
Eric Harris
Fluvoxamine taker
(Luvox)
Dylan Klebold
Columbine High
School massacre
Norepinephrine-dopamine reuptake inhibitors
Bupropion
安非他酮
• Glaxo Wellcome product
• Inhibits NE, DA and serotonin reuptake
• No weight gain or sexual dysfunction
Serotonin-norepinephrine reuptake inhibitors
度洛西汀
文拉法辛
Used for depression and generalized anxiety disorder
obsessive compulsive disorder
panic attacks
neuropathic pain (duloxetine)
Adverse effects: GI upset, headache, insomnia
Monoamine Oxidase Inhibitors (MAOIs)
MAO:
---Regulates free
intraneuronal concentration
of NE or 5-HT
---Regulates inactivation of
endogenous and ingested
amines
Side effects: few
anticholinergic,
adrenergic side effects
but toxicity associated
with dietary interactions
(tyramine)
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
• Enuresis: 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 Therapy
St. 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
Appendix
Drugs for mania
- Lithium carbonate
- Antiphsychotics
- Antiepileptics
- Calcium channel blockers
Appendix
Drugs for mania
Lithium 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.
Therapeutic range of lithium
Disease or condition
Therapeutic range
Acute mania
0.5-1.2 mmol/L
1.2-1.5 mmol/L may be required in selected patients
Prophylaxis of mania and/or depression
0.6-0.8 mmol/L
Concentration-related toxicity of lithium
Potential side effects under therapeutic concentrations: Agitation, cogwheel 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
disease (PD)
Tremor of one hand
Parkinsonism:
-Muscle rigidity
-Tremor
-Bradykinesia
(slowness of
motion), or even
akinesia (loss of
motor function)
-Postural instability
(propulsion,
retropulsion).
Dopaminergic neuronal loss in the substantia nigra
Substantia nigra
(striatum)
Substantia nigra
Imbalance of DA/ACh neuronal functions in
extrapyramidal system of Parkinson’s disease
Dopamine
Acetylcholine
How to reach the desired goal of
pharmacological therapies for 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)
Note: All therapies treat the symptoms of the disease;
none is neuroprotective and none slows the progression of the disease
How to increase dopamine synthesis capacity?
Provide DA precursor: L-DOPA (Levodopa )
OH
OH
OH
Rationale for L-DOPA Precursor
Loading:
OH
(AAAD)
L-DOPA decarboxylase
B6
O
• Striatal dopamine levels are low OH NH
L-Dopa
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.
2
NH2
Dopamine
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.
BBB
息
宁
Periphery
CNS
L-DOPA
L-DOPA
AAAD
AAAD
Carbidopa
－
dopamine
Peripheral adverse effects
dopamine
Therapeutic effects
＋
What are the major adverse effects of L-DOPA?
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, akinesia alternates improved mobility).
• Dyskinesia (months to years after, up to 80%,
increase of involuntary movements: chorea, ballismus,
athetosis, dystonia, myoclonus, tics, and tremor, any
part of the body may be involved).
How to reduce peripheral metabolism of L-DOPA?
-- peripheral COMT inhibition
HO
O
H
HO
C N
C C
CN
O2N
Entacapone
• 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
BBB
息
宁
3-OMD
Periphery
CNS
L-DOPA
L-DOPA
Entacapone
AAAD
AAAD
Carbidopa
－
dopamine
Peripheral adverse effects
dopamine
Therapeutic effects
＋
II. How to activate post-synaptic DA receptors?
- Dopamine receptor agonists
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)
Bromocriptine
N
(t1/2 ~ 8 -12 h)
罗平尼咯和普拉克索
N
Can be used as monotherapy for mild
Ropinrole H
parkinsonism, or combined with levodopa for
N
advanced disease, permitting the dose of
H2N
S
levodopa to be reduced and smoothing out
response fluctuations and dyskinesias.
Pramipexole
O
N
H
麦角生物碱类
Ergot Alkaloids (background)
-isolated from the fungus
Claviceps purpurea found on rye
and wheat and other grains.
-ergotism can cause nausea, and
mild symptoms: diarrhea
severe 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
What are the major adverse effects of
DA receptor agonists?
• 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) )
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
CH
N
Selegiline
Rasagiline
• 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)
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.
Muscarinic Receptor Antagonists
N
NCH2CH2COH
Trihexyphenidyl
CH3
C 6H 5
OCH
Benztropine C6H5
• 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
V. How to increase DA release?
NH2
Amantadine
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
DRUG THERAPY
Review
• 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)
Drug-Induced Parkinsonism
• 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.
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
Crude opium
Opium flowers
Collecting resin
of opium poppy
Seeds of
opium poppy
1. Classification of opiates
• 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.
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. Opioid receptors
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 antiinflammatory effect of opioids.
C
Immune cells: immune depression
2. Opioid receptors
2.2 Signal transduction:
In the Spinal Cord
2. Opioid receptors
In the Brain Stem
3. Opioids
Summary of opioid analgesics and antagonists:
Strong agonists: fentanyl, heroin, pethidine, methadone,
morphine
Moderate agonists: codeine
Mixed agonist-antagonists: pentazocine
Antagonists: naloxone, naltrexone
Mainly agonist action at μ receptors,
but some actions on other receptors
•Morphine
•Heroin
•Codeine
•Fentanyl
⊕
μ opioid
receptor
⊕
κ opioid
receptor
Agonist action at κ receptors,
with partial antagonist action
at μ receptors
•Pentazocine
⊕
 opioid
receptor
Analgesia
Analgesia
Analgesia
Respiratory depression Sedation/dysphoria
Euphoria/sedation
Pupil constriction
Physical dependence
Decreased GI motility
Antagonist act at μ, κ,  receptors
Pupil constriction
•Naloxone
•Naltrexone
Efficacy
high
Addiction/abuse
low
Morphine Pethidine
Methadone
Fentanyl
Codeine
A comparison of the maximum efficacy and
addiction/abuse liability of commonly used
narcotic analgesics
Time to peak effect
Duration of action
Morphine
Pethidine
Fentanyl
20min
4 hours
15min
2 hours
5min
45min
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
不良反应
用其他药无效的急性锐痛
易成瘾，抑制呼吸
慢性钝痛
无成瘾性及呼吸抑制
4. Morphine
B Euphoria:
- Produces a powerful sense of contentment and wellbeing 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. Pharmacodynamics- 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. 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).
Druggy
Malformation
4. Morphine
4.4 Contraindications:
• Women during labor or lactation
• New-born infants
• Chronic obstructive pulmonary disease (COPD)
• Asthma
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