Pharmacology of the nervous system Shi-Hong Zhang ( 张世红 ), PhD Dept. of Pharmacology, School of Medicine, Zhejiang University [email protected]

Pharmacology of the nervous system

Shi-Hong Zhang (张世红 ), PhD Dept. of Pharmacology,

School of Medicine, Zhejiang University [email protected]

•Cholinergic Pharmacology

•Adrenergic Pharmacology

Pharmacology of efferent nervous system

Adrenergic Receptor Antagonists

receptor antagonists:

nonselective: short acting (phentolamine 酚妥拉明 )

long acting (phenoxybenzamine 酚苄明 )

selective: 1 antagonists (prazosin 哌唑嗪 )

2 antagonists (yohimbine 育亨宾 )

β receptors antagonists:

nonselective: with ISA (pindolol 吲哚洛尔 )

without ISA (propranolol普萘洛尔 )

β1 antagonists: with ISA (acebutolol 醋丁洛尔 )

without ISA (atenolol 阿替洛尔 )

/β receptor antagonists: labetalol 拉贝洛尔 , carvedilol 卡维地洛

receptor antagonists

Phentolamine 酚妥拉明

N

NCH3

HO

N CH2

H

Pharmacological effects(1) Vasodilatation

Blocking 1 receptor: vasodilation in both arteriolar

resistance vessels and veins

(2) Cardiac stimulation

Reflex; blocking 2 receptor ～ NE release (3) Cholinergic and histamine-like effects

Contraction of GI smooth muscles,

Gastric acid secretion

Competitive, nonselective

Clinical uses

(1) Decrease blood pressure• Hypertension from pheochromocytoma嗜铬细胞瘤 (short term use). • Pre- and post-operation of pheochromocytoma

• Diagnostic test for pheochromocytoma

(2) Peripheral vascular diseases• Acrocyanosis (手足发绀 ), Raynaud’s disease雷诺氏病(3) Local vasoconstrictor extravasations

(4) Improve microcirculation: shock with pulmonary edema

(5) Acute myocardial infarction and obstinate congestive heart failure

Major Adverse effects – postural hypotension, reflex tachycardia, arrhythmia, angina pectoris, GI reactions

Phentolamine

Pheochromocytoma is a rare catecholamine-secreting tumor derived from chromaffin cells of the adrenal medulla that produces excess epinephrine.

• Hypertension & Crises• Elevated Metabolic Rate

-heat intolerance-excessive sweating-weight loss

• Temporarily manage with -adrenergic antagonists (1 & ±)

Pheochromocytoma

• Irreversible, nonselective ( 1 and 2 antagonists )

• Long-acting

• Similar to phentolamine in actions and clinical uses

Phenoxybenzamine 酚苄明

1 receptor antagonists

• Prazosin: treatment for hypertension, CHF

• Tamsulosin: 1A blocker, for benign prostate

hypertrophy

2 receptor antagonists

• Yohimbine: for research use, ED, diabetic

neuropathy

Adrenergic Receptor Antagonists

receptor antagonists:

nonselective: short acting (phentolamine 酚妥拉明 )

long acting (phenoxybenzamine 酚苄明 )

selective: 1 antagonists (prazosin 哌唑嗪 )

2 antagonists (yohimbine 育亨宾 )

β receptors antagonists:

nonselective: with ISA (pindolol 吲哚洛尔 )

without ISA (propranolol 普萘洛尔 )

β1 antagonists: with ISA (acebutolol 醋丁洛尔 )

without ISA (atenolol 阿替洛尔 )

/β receptor antagonists: labetalol 拉贝洛尔 , carvedilol 卡维地洛

General properties:ADME

• First-pass elimination, especially for those with high lipid solubility (eg普萘洛尔 ).

• lower bioavailability: propranolol• Hepatic metabolism and renal excretion

hepatic and renal functions alter the effects of the drugs and result in large individual variation

• Dose individualization is necessary.


Pharmacological effects(1) receptor blockadeA. Cardiovascular effects：• Depressing the heart: reduction in HR, A-V

conduction, automaticity, cardiac output, oxygen consumption

• Hypotension: peripheral blood flow , hypotensive effect in hypertensive patients


(1) receptor blockadeB. Bronchial smooth muscles• induces bronchial smooth muscle contraction in

asthmatic patients

C. Metabolism• lipolysis , glycogenolysis, potentiating insulin

effects ~ hypoglycemia

D. Renin secretion• decreasing secretion of renin


(2) Intrinsic sympathomimetic effects Partial agonists: e.g. pindolol, acebutolol (weaker

cardiac inhibition and bronchoconstriction; cardiac stimulation in larger doses)

(3) Membrane-stabilizing effects Larger doses of some drugs: quinidine-like effects, Na+

channel blockade

(4) Others• Lowering intraocular pressure;• Inhibiting platelet aggregation;• Inhibiting conversion from T4 to T3


Circulation of Aqueous humorCirculation of Aqueous humor

Clinical uses(1) Arrhythmia: supraventricular, sympathetic

activity (2) Hypertension

(3) Angina pectoris and myocardial infarction

(4) Chronic heart failure

(5) Others: hyperthyroidism, migraine, glaucoma (timolol)...


Adverse effects(1) Heart depression: contraindicated in heart

failure, severe A-V block, sinus bradycardia

(2) Worsening of asthma: contraindicated in bronchial asthmatic patients

(3) Withdrawal syndrome ： up-regulation of the receptors

(4) Worsening of peripheral vascular constriction

(5) Others ： central depression, hypoglycemia, sexual dysfunction, etc.


• 1, 2 receptor blocking

• no intrinsic activity• first-elimination after oral administration,

individual variation of bioavailability

Propranolol

Timolol• For the treatment of glaucoma (wide-angle)

1receptor antagonists, no intrinsic activity

• atenolol : longer t1/2, once daily

• usually used for the treatment of hypertension

Atenolol, Metoprolol

α, receptor antagonists

• α, β receptor blocking, β> α

• usually used for treatment of hypertension, angina pectoris, moderate CHF.

Labetalol, Carvedilol

SummaryAgonist Receptor

specificityTherapeutic uses

epinephrine 1,21,2

• Acute asthma,• Anaphylactic(过敏性 ) shock,• in local anesthetics to

increase duration of action

norepinephrine 1,21)

• shock

isoproterenol 1,2 • Asthma• As cardiac stimulant

dopamine Dopaminergic,

• Shock,• Congestive heart failure

dobutamine • Heart failure

SummaryAgonist Receptor


Ephedrine(麻黄碱 )

•asthma•as a nasal decongestant

Metaraminol (间羟胺 )

•Shock•hypotension

Phenylephrine (苯肾上腺素 )

•supraventricular tachycardia •glaucoma•as a nasal decongestant

Methoxamine (甲氧胺 )

•supraventricular tachycardia

Clonidine •hypertension

SalbutemolTerbutalineRitodrine

•Asthma•Premature labor

SummaryAntagonist Receptor


PhentolaminePhenoxybenz-

amine (酚苄明 )

• pheochromocytoma• Peripheral vascular diseases• Local vasoconstrictor

extravasation

prazosin • hypertension

propranolol • Hypertension• Glaucoma• Migraine• Hyperthyroidism• Angina pectoris• Myocardial infarction

timolol • Glaucoma • hypertension

AtenololMetoprolol

• hypertension

labetalol • hypertension

Drugs That Act in the

Central Nervous System

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

excitation

inhibition

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:

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. Benzodiazepines Benzodiazepines

Disassociation of effect and half-life time

1. 1. ADMEADME

Classification according to action duration

Short-acting: triazolam, laorazepam, oxazepam, etc

Medium and long-acting: diazepam, nitrazepam,

chlordiazepoxide, flurazepam etc

(4) Urinary excretion


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


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


(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.


(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


3. Action 3. Action MechanismsMechanisms

(1) Sites of action: mainly acts on limbic system (anxielytic) and midbrain reticular formation (hypnotic).



(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 confusion

ataxia; 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 misuse

Withdrawal syndrome (shorter acting agents): restlessness, anxiety, weakness, orthostatic hypotension and generalized seizures


(3) Others Respiratory and CVS reactions

Teratogenic effects (Pharmaceutical Pregnancy Category D or X)

(4) ContraindicationsMyasthenia gravis (重症肌无力 )

Infants < 6 months

Pregnant and lactation mothers

Elderly with heart/lung/liver/kidney dysfunction

Workers requiring mental alertness and fine motor coordination


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. Barbiturates Barbiturates

• 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


3. Adverse effects

(4) Acute poisoning

---supporting therapies: oxygen inhalation, unblocked respiratory tract (tracheootomy), central stimulants

---alkalizing urine

---hemodialysis


Marilyn Monroe (1926-1962)

• Chloral hydrate

Sedative-hypnotic effects

Anticonvulsant effect: children (anal administration)

• Buspirone: anxiolytic, minimal abuse liability

• zolpidem唑吡坦 , zaleplon扎来普隆 : short-term

hypnotics, selective BZ binding, for patients with

difficulties in falling asleep.

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

Source of 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 frothing

Jerking 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

Current status of epilepsy treatment

• 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 • Zonisamide • 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 / kg

www.boomer.org/c/p4/c21/c2103.html

http://en.wikipedia.org/wiki/Focal_seizures

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 but not sedation,

increase in seizure rate.

• Local irritating (alkaline): gingival hyperplasia, GI upset, phlebiitis• Hematologic complications - Megaloblastic anemia: folic acid loss

- Agranulocytosis (粒细胞缺乏 )• Idiosyncratic or allergic reactions

- Rash, up to 10%, can be very serious - stop drug- Fever- Hepatitis

• Skeleton: osteomalaacia (骨软化 , Vit D degradation↑)

• Others: birth defects (fetal malformations, class D), hirsutism

hirsutismGingival hyperplasia

Phenytoin side effects

Carbamazepine• Mechanisms: blockade of

Na+ and Ca2+ channels, potentiation of GABA transmission

• Half life = 8-12 hours• 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 others

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.

http://en.wikipedia.org/wiki/Simple_partial_seizure

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– 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 ).

http://en.wikipedia.org/wiki/Complex_partial_seizure

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


• 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.


Documents

Pharmacology of the nervous system Shi-Hong Zhang ( 张世红 ), PhD Dept. of Pharmacology, School of Medicine, Zhejiang University [email protected]