Drugs That Act in the Central Nervous System

Dept. of PharmacologyShi-Hong Zhang, Ph.D,

shzhang713@zju.edu.cn

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

excitationinhibition

Balance in the CNS function

Classification of CNS drugs

• Sedative-hypnotics • Antiepileptic and anticonvulsive drugs• Drugs for Parkinson’s disease• Analgesics and anesthetics• Central stimulants

Neurological:

Classification of CNS drugs

• Antipsychotic drugs• Antidepressant and antimanic drugs• Drugs for dementia

Psychological:

NOTE: Besides to treat neuropsychological diseases, CNS drugs are important tools for studying CNS physiology and pathogenesis of disease.

Sedative-Hypnotic Drugs

- 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.

Graded dose-dependent effect

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)

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

Disassociation of effect and half-life time

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

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

NREM

Stages 3

Stages 3 and 4 are deep sleep.Growth hormone is released during these stages.

Slow wave sleep

BZs

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

(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

(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

3. Action 3. Action MechanismsMechanisms(1) Sites of action: mainly acts on limbic system

(anxielytic) and midbrain reticular formation (hypnotic).

A.A. BenzodiazepinesBenzodiazepines

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

γ subunit

(2) Interaction with GABAA receptor

Hyperpolarization

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

(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

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

• increase the duration of the GABA-gatedchloride ion channel openings• GABA-mimetic at high dose – GABA independent efficacy

Graded dose-dependent depressive effect of sedative- hypnotics on central nervous system function

Benzodiazepines

Barbiturates

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

3. Adverse effects

(4) Acute poisoning---supporting therapies: oxygen inhalation, unblocked respiratory tract (tracheootomy), central stimulants---alkalizing urine---hemodialysis

B.B. BarbituratesBarbiturates

Marilyn Monroe (1926-1962)

• Chloral hydrateSedative-hypnotic effectsAnticonvulsant effect: children (anal administration)

• Buspirone: anxiolytic, minimal abuse liability

• zolpidem, zaleplon: hypnotics, selective BZ binding

C. Other sedative-hypnotic drugs

• Antipsychotics• Antidepressant drugs • Antihistaminic agents• Ethanol• Melatonin (pineal hormone)

C. Other sedative-hypnotic drugs

Summary of clinical uses of sedative-hypnotics

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

International Classification of Epileptic Seizures:

Partial Onset Seizures

– Simple Partial

– Complex Partial (consciousness is affected)

– Partial Seizures with secondary generalization

Sourceof seizure

International Classification of Epileptic Seizures: Primary Generalized Seizures

–Absence (Petit Mal)–Generalized

Tonic+Clonic (Grand Mal)

–Tonic–Atonic–Clonic and myoclonic

Stereotypical complex partial seizures

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

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.

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

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

Effects of three antiseizure drugs on sustained high-frequency firing of action potentials by

cultured neurons.

Mechanisms of AEDs

• Modification of ionic conductance.- Na+

- K+

- Ca2+

• Enhancement of GABAergic (inhibitory) transmission

• Diminution of excitatory transmission

Drugs which act on Na+ channel

• Phenytoin• Carbamazepine• Oxcarbazepine• Lamotrigine

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

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)

• 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

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

hirsutismGingival hyperplasia

Phenytoin side effects

Mephenytoin: more severe adverse effects

Ethotoin: Less effective

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)

• 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

Oxcarbazepine --- less effective --- improved toxicity profile

(fewer hypersensitivity reactions less hepatic enzyme induction)

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

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

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)

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.

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

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

Drugs which affect Kainate and AMPA receptors

• Topiramate• Zonisamide

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

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)

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).

When to initiate treatment?

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

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

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

Decreased risk• Idiopathic cause• Generalized seizure• No family history of epilepsy• Normal electroencephalogram• Normal findings on neurologic examination

Initiation of Treatment

• 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

Initiation of Treatment

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.

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

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

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

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

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

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 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

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

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

(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

(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 hiccoughbut 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• S eizures• Endocrine - prolactin elevations• Drooling• Weight gain

Chlorpromazine

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)

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” 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

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.

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.

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

TCAsMechanisms: Non-selective monoamines (mainly NE and 5-HT) reuptake inhibitorsClinical 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 disorderobsessive compulsive disorderpanic attacksneuropathic 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 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

- 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

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

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

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

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 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

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)

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

NO

H

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)

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

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

• 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)

- 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 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)

• 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