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Drugs That Act in the Central Nervous System
Dept. of PharmacologyShi-Hong Zhang, Ph.D,
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Central Nervous System Diseases (Neuropsychological diseases,神经精神疾病)
• Causes:-Trauma-Infections-Degeneration-Structural defects-Tumors-Autoimmune disorders-Ischemia-etc
• Diseases:-Encephalitis (脑炎)
-Alzheimer’s Disease (老年痴呆)
-Parkinson’s Disease(帕金森病)
-Multiple Sclerosis (多发性硬化)
-Insomnia (失眠)
-Epilepsy(癫痫)
-Pain(疼痛)
-Stroke(中风)
-Schizophrenia (精神分裂症)
-Depression(抑郁症)
-Mania(躁狂症)
- etc
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excitationinhibition
Balance in the CNS function
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Classification of CNS drugs
• Sedative-hypnotics • Antiepileptic and anticonvulsive drugs• Drugs for Parkinson’s disease• Analgesics and anesthetics• Central stimulants
Neurological:
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Classification of CNS drugs
• Antipsychotic drugs• Antidepressant and antimanic drugs• Drugs for dementia
Psychological:
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NOTE: Besides to treat neuropsychological diseases, CNS drugs are important tools for studying CNS physiology and pathogenesis of disease.
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Sedative-Hypnotic Drugs
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- is characterized by excessive, exaggerated anxiety and worry about everyday life events with no obvious reasons for worry;- can be extremely debilitating, having a serious impact on daily life.
Anxiety
Insomnia:
-1-5%, more in old women; - trouble in falling asleep or too easily to be waken up; - can be primary or secondary; - harmful to daily life: excessive daytime sleepiness and a lack of energy, feel anxious, depressed, or irritable.
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Graded dose-dependent effect
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Chemical classification• Benzodiaazepines: diazeepam (安定), nitraazepam (硝西泮),
oxaazepam (奥沙西泮), estazolam (艾司唑仑), triazolam (三唑 仑), flunitrazepam (氟硝西泮),etc (with same nucleus and
different substituents)• Barbiiturates: pentobarbital(戊巴比妥), phenobarbital (苯巴
比妥), thiopental (硫喷妥), etc• Others: buspirone (丁螺环酮), chloral hydrate (水合氯醛),
meprobamate (甲丙氨酯), etc• Antipsychotic (e.g. chlorpromazine), antidepressant drugs
(e.g. amitriptyline) and certain antihistaminic agents (e.g. diphenhydramine)
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1. 1. ADMEADME
(1) Oral absorption(2) Lipid solubility-dependent distribution (across
BBB), placcental penetrabbility (effect on fetus)(3) Hepatic metabolism ---active metabolites
A.A. BenzodiazepinesBenzodiazepines
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Disassociation of effect and half-life time
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1. 1. ADMEADME
Classification according to action durationShort-acting: triazolam, laorazepam, oxazepam, etcMedium and long-acting: diazepam, nitrazepam,
chlordiazepoxide, flurazepam etc
(4) Urinary excretion
A.A. BenzodiazepinesBenzodiazepines
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2. 2. Pharmacological effects and clinical usesPharmacological effects and clinical uses
(1) Reduction of anxiety: at small doses, used as anxiolytics (not work on schizophrenia)
(2) Sedative-hypnotic effects---- at relatively higher doses-- no anesthetic effect-- no enzyme induction-- increase stage 2 of NREM, no remarkable effect on REM, decrease slow wave sleep
A.A. BenzodiazepinesBenzodiazepines
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NREM
Stages 3
Stages 3 and 4 are deep sleep.Growth hormone is released during these stages.
Slow wave sleep
BZs
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2. 2. Pharmacological effects and clinical usesPharmacological effects and clinical uses
(2)Sedative-hypnotic effects-- used for insomnia and preanesthetic medication
(as adjuvant to anesthetics)(3) Antiepileptic and anticonvulsant effects
-- inhibit epileptiform activity
-- used for seizures, status epilepticus (i.v.),
convulsion
A.A. BenzodiazepinesBenzodiazepines
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(4) Centrally acting muscle relaxant effect-- relaxing the spasticity of skeletal muscle, probably
by increasing presynaptic inhibition in the spinal cord.
-- used for the treatment of skeletal muscle spasms caused by central or peripheral diseases.
A.A. BenzodiazepinesBenzodiazepines
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(5) Others--dose-dependent anterograde amneesic effects ( i.v.)
- for unpleasant examination or therapy (cardioversion, endoscope, etc)
--respiratory and CVS effects (central inhibition)
-- alleviate the withdraw syndromes
A.A. BenzodiazepinesBenzodiazepines
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3. Action 3. Action MechanismsMechanisms(1) Sites of action: mainly acts on limbic system
(anxielytic) and midbrain reticular formation (hypnotic).
A.A. BenzodiazepinesBenzodiazepines
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A.A. BenzodiazepinesBenzodiazepines
(2) Interaction with GABAA receptor-- Increase the frequency of GABA-induced
chlorine channel-opening events-- GABA dependent effect
3. Action 3. Action MechanismsMechanisms
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γ subunit
(2) Interaction with GABAA receptor
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Hyperpolarization
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4. Adverse effects(1) Central depression
Most common: drowsiness and confusionataxia; cognitive impairment (hangover effect)Additive with other CNS depressant drugs
Antagonized by BZ receptor antagonist flumazenil(2) Tolerance: lethal dose is not altered
(3) Dependence: compulsive misuseWithdrawal syndrome (shorter acting agents): restlessness, anxiety, weakness, orthostatic hypotension and generalized seizures
A.A. BenzodiazepinesBenzodiazepines
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(3) OthersRespiratory and CVS reactions Teratogenic effects (Pharmaceutical Pregnancy Category D or X)
(4) ContraindicationsMyasthenia gravis (重症肌无力)Infants < 6 monthsPregnant and lactation mothersElderly with heart/lung/liver/kidney dysfunctionWorkers requiring mental alertness and fine motor
coordination
A.A. BenzodiazepinesBenzodiazepines
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1. ADME- hepatic enzyme inducer - alkalizing urine (sodium bicarbonate): excretion
2. Pharmacological effects and clinical uses(1) Sedative-hypnotic effects - REM decrease(2) Antiepileptic and anticonvulsant effects(3) Preanesthetic medication
B.B. BarbituratesBarbiturates
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• increase the duration of the GABA-gatedchloride ion channel openings• GABA-mimetic at high dose – GABA independent efficacy
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Graded dose-dependent depressive effect of sedative- hypnotics on central nervous system function
Benzodiazepines
Barbiturates
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3. Adverse effects
(1) Central depression: after (hangover) effect
(2) Tolerance and dependence: repetitive use, long- term use, REM rebound
(3) Porphyria (enhances porphyrin synthesis): anemia, photosensitive skin injury
B.B. BarbituratesBarbiturates
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3. Adverse effects
(4) Acute poisoning---supporting therapies: oxygen inhalation, unblocked respiratory tract (tracheootomy), central stimulants---alkalizing urine---hemodialysis
B.B. BarbituratesBarbiturates
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Marilyn Monroe (1926-1962)
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• Chloral hydrateSedative-hypnotic effectsAnticonvulsant effect: children (anal administration)
• Buspirone: anxiolytic, minimal abuse liability
• zolpidem, zaleplon: hypnotics, selective BZ binding
C. Other sedative-hypnotic drugs
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• Antipsychotics• Antidepressant drugs • Antihistaminic agents• Ethanol• Melatonin (pineal hormone)
C. Other sedative-hypnotic drugs
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Summary of clinical uses of sedative-hypnotics
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Antiepiletpic Drugs (AEDs)
-----Epilepsy is a chronic disorder characterized by recurrent seizures, which are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons
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International Classification of Epileptic Seizures:
Partial Onset Seizures
– Simple Partial
– Complex Partial (consciousness is affected)
– Partial Seizures with secondary generalization
Sourceof seizure
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International Classification of Epileptic Seizures: Primary Generalized Seizures
–Absence (Petit Mal)–Generalized
Tonic+Clonic (Grand Mal)
–Tonic–Atonic–Clonic and myoclonic
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Stereotypical complex partial seizures
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Tonic phase
Clonic phase
CyanosisCry
Salivary frothingJerking of the limbs
Post-ictal phase
Patient feels lethaargic and confused after seizuresOften sleeps
Loss of consciousness, Fall, crying, and generalized tonic stiffeningoften with bladder incontinence
Simultaneous bilateral cortical seizure attack
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Epilepsy treatment
• Epilepsy affects 1% population worldwide• Drug treatment is the main approach.• ~20-30% of patients develop refractory
epilepsy.• New drugs and new approaches are
needed.
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AEDs Effective as Monotherapy (Single Agent)
Partial (Localization Related)
• Phenytoin• Carbamazepine• Valproate• Oxcarbazepine• Lamotrigine• Topiramate• Gabapentin
Generalized
• Phenytoin• Carbamazepine • Valproate
– (GTC and absence)• Ethosuximide
- (absence)• Topiramate
– (GTC)• Lamotrigine
– (absence)
Bold= new generation AED
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New AEDs effective as adjunctive treatment for refractory epilepsy
Partial
• Topiramate• Levetiracetam• Pregabalin • Z onisamide• Oxcarbazepine
• Lamotrigine• Gabapentin• Tiagabine
Generalized
• Topiramate• Levetiracetam• Lamotrigine
– Data from randomized placebo controlled trials
Drugs in red are generally considered high potency
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Effects of three antiseizure drugs on sustained high-frequency firing of action potentials by
cultured neurons.
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Mechanisms of AEDs
• Modification of ionic conductance.- Na+
- K+
- Ca2+
• Enhancement of GABAergic (inhibitory) transmission
• Diminution of excitatory transmission
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Drugs which act on Na+ channel
• Phenytoin• Carbamazepine• Oxcarbazepine• Lamotrigine
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Phenytoin
• Effective against partial seizures and generalized tonic-clonic seizures
• Non-linear kinetics• Therapeutic range = 10-20
ug/ml–Levels above 20 cause ataxia and nystagmus (眼球震颤)
• Half life = 12-24 hours, slow effect
• Hepatic metabolism–CYP3A enzyme pathway
Oral Dose: about 5 mg / kgwww.boomer.org/c/p4/c21/c2103.html
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Phenytoin -----Mechanisms of action
• Binding to and hence prolonging the status of inactivated state of Na+
channels (main mechanism)• Blocking L- and N- type Ca2+ channels
(inhibits release of transmitters, stabilizes membrane)
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• Chronic neuropathic pain: trigeminal neuralgia (三叉神经痛), sciatica (坐骨神
经痛), glossopharyngeal neuralgia (舌
咽神经痛)
• Arrhythmia--b anti-arrhythmia drug
Phenytoin ---Other uses
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Phenytoin side effects• CNS: nystagmus, diplopia, ataxia, depression• Local irritating (alkaline): gingival hyperplasia, GI upset,
phlebitis• Hematologic complications
- Megaloblastic anemia: folic acid loss- Agranulocytosis
• Idiosyncratic or allergic reactions- Rash, up to 10%, can be very serious - stop drug- Fever- Hepatitis
• Skeleton: osteomalacia (骨软化, Vit D degradation↑)• Others: birth defects (fetal malformations, class D), hirsutism
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hirsutismGingival hyperplasia
Phenytoin side effects
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Mephenytoin: more severe adverse effects
Ethotoin: Less effective
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Carbamazepine
• Mechanisms: blockade of Na+ and Ca2+ channels, potentiation of GABA transmission
• Half life = 8-12 hours (steady state)
• Like phenytoin, metabolized by CYP3A pathway (inducer itself)
• Effective against partial and generalized tonic- clonic seizures, trigeminal neuralgia and mania
• Safety and Toxicity–peak effect- diplopia, ataxia–rash 5-10%–rare marrow suppression
aplastic anemia and agranulocytosis
–rare hepatitis–frequent hyponatremia at high dose–fetal malformations (class D)
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• Dose in Adults– 200 mg once a day – After several days, 200 mg
twice a day– Slowly titrate to 10 mg/kg
• Therapeutic = 6 -12 ug/ml
Watch for Rash!
Carbamazepine
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Oxcarbazepine --- less effective --- improved toxicity profile
(fewer hypersensitivity reactions less hepatic enzyme induction)
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Lamotrigine• Na+ channel blocker• Ca2+ channel blocker• Moderate effective against both
partial and generalized epilepsy (absence/myoclonic) as add-on or monotherapy
• Hepatic metabolism, significant drug interactions with valproate (CYP inhibitor) leads to twofold increase in half-life time (level and side-effects increase)
• Linear clearance• Half life -24 hours• Start 25 mg/day, titrate slowly to 300-
500 mg/day
• 10% risk of rash• Dizziness,
headache, diplopia, nausea, somnolence
• Class C in pregnancy, significantly lower than other
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Drugs acting at the chloride channel
• Benzodiazepines–Binds to BZD specific receptors
• Phenobarbital –Binds to barbiturate specific receptors
• Gabapentin– GABA analogue, alters GABA metabolism, release
and reuptake, effective as an adjunct against partial seizures and generalized tonic-clonic seizures
• Valproate –Decreases GABA degradation in presynaptic terminal
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Valproate • Broad spectrum:
- absence: ethosuximide first choice- generalized tonic-clonic- partial
• Blocks Na+ channels and NMDA receptors
• Increases GABA levels– Facilitates GAD– Inhibits GAT-1– Inhibits degradation of
GABA• dose = 15-20 mg/kg to start
using a TID schedule
• GI side effects (abdominal pain and heartburn)
• Obesity + Metabolic syndrome (weight gain, increased appetite, and hair loss)
• Hepatotoxicity, elevates ammonia (liver function monitoring required)
• Fine tremor• Serious neural tube (spina
bifida, split spine) and cardiac defects in fetus in 1% (Pregnancy Category D)
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During and After Valproate Therapy
It should be noted that valproate is an effective and popular antiseizure drug and that only a very small number of patients have had severe toxic effects from its use.
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Drugs which primarily affect potassium channel
• Levetiracetam– Blocks voltage gated K+
channels in hippocampus neurons
– Blocks kainate receptors – Affects GABA receptors– Blocks action potentials,
and paroxysmal depolarizing shifts
Madeja et al Neuropharamacology 2003
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Drugs which primarily affect potassium channel
Levetiracetam• Effective for partial
epilepsy with or without generalization
• High Potency-----75% reduction in
seizures in over 20% of refractory patients
• Few side effects except: – Somnolence, asthenia,
and dizziness– Pregnancy category C
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Drugs which affect Kainate and AMPA receptors
• Topiramate• Zonisamide
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Topiramate• Mechanisms -Multiple
– Blocks AMPA+kainate receptors
– Blocks Na+ and Ca2+ channels
– Potentiates GABA transmission
• Effective against both partial and generalized epilepsy
• Excreted primarily in urine• Start at 25 mg/day, titrate
to 300-500/day
• Behavioral /Cognitive problems common (somnolence, fatigue, dizziness, cognitive slowing, paresthesias, nervousness, and confusion)
• Low risk of rash• Causes weight loss• Class D in pregnancy (oral
clefts)• High Potency
----75% reductions in over 20% of refractory patients
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Drugs which affect calcium channels
Ethosuximide
• Mechanism– Blocks T-Ca2+ channels in thalamic neurons (T-type
calcium currents are thought to provide a pacemaker current in thalaamic neurons responsible for generating the rhythmic cortical discharge of an absence attack)
• Effective against absence seizures• Long half life time 40~50h• Effective dose range 750–1500 mg/d• Adverse effects: gastric distress (stomachache, nausea,
vomiting), CNS response (fatigue, dizziness, headache, euphoria, sleepiness, hiccup)
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Teratogenicity• All AEDs cause fetal
malformations in at least 6% of infants, such as neural tube defects, mouth malformation, cardiopathy.
• Highest risk with phenytoin, valproate, phenobarbital, and carbamazepine, etc (Class D drugs)
• Folate supplementation prevents neural tube defects (split spine, 脊柱裂).
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When to initiate treatment?
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Case Study: Initiation of Treatment
• A 22 year old female sustains a head injury with loss of consciousness
• Two years later she develops a single secondarily generalized tonic-clonic seizure
• MRI and EEG are normal
• You should
1. Instruct her not to drive. Report the event to the department of public health or DMV
2. Wait until a second seizure, and then initiate an AED
3. Initiate a pregnancy class C AED now.
4. Initiate, phenytoin, valproic acid, phenobarbital, or carbamazepine now
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Initiation of Treatment
• Consider all the facts. – After a first seizure, the risk of subsequent
epilepsy is 35% within 1-2 years– After a second seizure, the risk is over 90%
• It depends on the level of risk and the patient’s situation
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Initiation of Treatment
Increased risk• Known symptomatic cause• Partial seizures• Family history of epilepsy• Abnormal electroencephalogram (particularly
generalized spike-and-slow wave)• Abnormal findings on neurologic examination• Abnormal imaging findings
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Decreased risk• Idiopathic cause• Generalized seizure• No family history of epilepsy• Normal electroencephalogram• Normal findings on neurologic examination
Initiation of Treatment
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• the risk-benefit ratio of the anticonvulsant treatment must be carefully assessed in patients after a single seizure
• Avoid valproic acid in a woman of childbearing potential. Answer 4 is clearly a poor choice.
Initiation of Treatment
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Initiation of Treatment
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Antipsychotic agents
----Schizophrenia (精神分裂症), is a particular kind of psychosis characterized by a clear sensorium but a marked thinking disturbance
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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.
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Schizophrenia • Neurological Disorder - impaired ability to perceive,
understand & interpret the environment
• Impaired social and occupational function
• Behavioral Syndrome – predictable or not
• Etiology and biology remain unclear- familial tendency (heritability), DA and other neurotransmitters
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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 without full recovery--10% no remission
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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)
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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
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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.pdfFilm: One Flew Over the Cuckoo’s Nest (1975)
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Classification of antipsychotics
Typical:• Phenothiaazines (吩噻嗪类): chlorproomazine• T hioxanthenes (硫杂蒽类): chlorprothixene• Buutyrophenones (丁酰苯类): halopeeridolAtypical:• Clozapine, olanzapine, risperidone
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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 – 5-HT2 , D1, D2, M, H, αreceptor antagonist,
good– Risperidone – 5-HT2 and D2 receptor antagonist, good– Aripiprazole – partial agonist of D2 and 5-HT1 receptor
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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)
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Dopaminergic pathways in CNS and drugs for schizophrenia
A. mesolimbic and mesocortical pathwaysrelated with psychological activities and the
therapeutic effects of drugs.B. nigrostriatal pathway
related with extrapyramidal adverse effects of drugs
C. Tuberohypoophyseal pathwayrelated with hypothalamus endocrine adverse
effects of drugs
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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
Chlorpromazine1. 1. Pharmacological effectsPharmacological effects(1) Central effects(1) Central effects
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c) Poikilothermic effects (comparison with NSAIDs)-- hypothermic anesthesia-- artificial hibernation (with mepeeridine, promethazine)
d) Extrapyramidal effects (nigrostriatal pathway blockade)
-- primary adverse effectse) Potentiating the effects of central depressants
-- sedative-hypnotics, analgesics, general anesthetics, ethanol
Chlorpromazine
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(2) Effects on autonomic nervous system
a) Hypotensive effects
receptor blockade, postural hypotension
b) Anticholinergic effectsdry mouth, constipation, blurred vision, urinary
retention, increased intraocular pressure,etc.
Chlorpromazine
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(3) Endocrine effects (Tuberohypoophyseal pathway blockade)
Prolactin Estrogen, progestin, ACTH, growth hormone
Chlorpromazine
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2. Clinical uses
(1) Treatment and prevention of acute schizophrenia and mania
(2) Treatment of emesis and hiccoughbut ineffective on motion sickness
(3) Hypothermic anesthesia and artificial hibernation
combined with lowering room temperature
Chlorpromazine
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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
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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)
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3. Side effects• Sedation• Cardiac - lengthen QT interval• S eizures• Endocrine - prolactin elevations• Drooling• Weight gain
Chlorpromazine
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Haloperidol• High efficacy for positive symptoms• Weaker sedative effect• W eaker
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)
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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.
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“Atypical” AntipsychoticsMany 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
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Case study --continuedW.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.
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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
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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.
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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
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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
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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.
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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.
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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
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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
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TCAsMechanisms: Non-selective monoamines (mainly NE and 5-HT) reuptake inhibitorsClinical uses: depression, anxiety, obsessive compulsive disorder, panic disorder, neuropathic pain, enureesis
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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
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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
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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
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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
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Bupropion
• Glaxo Wellcome product• Inhibits NE, DA and serotonin reuptake• No weight gain or sexual dysfunction
安非他酮
Norepinephrine-dopamine reuptake inhibitors
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文拉法辛
Serotonin-norepinephrine reuptake inhibitors
度洛西汀
Used for depression and generalized anxiety disorderobsessive compulsive disorderpanic attacksneuropathic pain (duloxetine)
Adverse effects: GI upset, headache, insomnia
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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
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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.
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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
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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
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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
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Alternative Treatments for Depression
• Herbal Therapy- St. Johns wort (Hypericum perforatum)
• Electroconvulsive Therapy • Transcranial Magnetic Stimulation• Exercise
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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
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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
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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)
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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
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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
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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
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- Lithium carbonate - Antiphsychotics - Antiepileptics - Calcium channel blockers
AppendixDrugs for mania
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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
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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
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ConcentrationConcentration--related toxicity of lithiumrelated 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
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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
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ParkinsonParkinson’’s 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
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Dopaminergic neuronal loss in the substantia nigra
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Substantia nigra Substantia nigra
(striatum)
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Dopamine
Acetylcholine
Imbalance of DA/ACh neuronal functions in extrapyramidal system of Parkinson’s disease
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Different approaches including: I Increases in dopamine synthesis capacity (L-DOPA)II Direct activation of post-synaptic receptorsIII Inhibition of dopamine metabolism (MAOIs)IV Alteration of the interaction/balance with other
neurotransmitters (Ach)V Dopamine releasersVI 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
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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 BBBand, 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)
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What happens to L-DOPA in the periphery? L-DOPA peripheral metabolism
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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.
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dopamine
Periphery CNS
L-DOPA
BBB
L-DOPA
dopamine
AAADAAAD
Peripheral adverse effects Therapeutic effects
-
+
Carbidopa
息
宁
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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?
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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?
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• 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
NO
H
Entacapone
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dopamine
Periphery CNS
L-DOPA
BBB
L-DOPA
dopamine
AAADAAAD
Peripheral adverse effects Therapeutic effects
-
+
Carbidopa
息
宁
3-OMD
Entacapone
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1st generation agonists: (ergot derivatives)bromocriptine* (D2 agonist) (t1/2 ~ 12 h)pergolide* (D2 /D3 agonist)(t1/2 ~ 24 h)
2nd generation agonists:ropinirole (t1/2 ~ 6 h) (D2 /D3 agonist)pramipexole (D2 agonist)
(t1/2 ~ 8 -12 h)
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
NH
Pramipexole
Bromocriptine
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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
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• 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?
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Dopamine Agonists
Apomorphine (Apokyn)
- 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
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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
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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.
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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
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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
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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)
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• 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
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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
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Photograph showing an electrode being inserted during deep brain stimulation