Drugs affecting peripheral nervous system San-Hua Fang, PhD 方三华 Dept. of Pharmacology, School of Medicine, Zhejiang University [email protected]

Drugs affecting Drugs affecting peripheralperipheralnervous systemnervous system

SanSan--HuaHua FangFang, PhD, PhD方三华方三华

Dept. of Pharmacology, Dept. of Pharmacology, School of Medicine, Zhejiang UniversitySchool of Medicine, Zhejiang University

[email protected]@zju.edu.cn

Adrenoceptor Adrenoceptor antantagonistsagonists

（（ 11 ）） receptor antagonistsreceptor antagonists 112 2 receptor antagonists:receptor antagonists:

short-acting:short-acting: phentolamine phentolamine(( 酚妥拉明酚妥拉明 ))

long-acting:long-acting: phenoxybenzamine phenoxybenzamine (( 酚苄明酚苄明 ))

1 1 receptor antagonists:receptor antagonists: prazosinrazosin(( 哌唑嗪）哌唑嗪）

2 2 receptor antagonists:receptor antagonists: yohimbineohimbine （育亨（育亨宾）宾）

Drug actions and classificationDrug actions and classification

Adrenoceptor Adrenoceptor antantagonistsagonists （（ 22 ）） receptor antagonistsreceptor antagonists 112 2 receptor antagonists:receptor antagonists: propranololpropranolol （普萘洛（普萘洛

尔）尔） 1 1 receptor antagonists:receptor antagonists: atenololatenolol （阿替洛尔）（阿替洛尔） 2 2 receptor antagonists:receptor antagonists: butoxaminebutoxamine （（丁氧胺）

（（ 33 ）） , , receptor antagonists receptor antagonists • labetalollabetalol （拉贝洛尔）（拉贝洛尔）

Drug actions and classificationDrug actions and classification

Epinephrine reversalEpinephrine reversal

（（ adrenaline reversaladrenaline reversal ））

BP

antagonistantagonistepinephrineepinephrine epinephrineepinephrine

• competitive, competitive, nonselective ((11, , 2 2 receptor receptor

antagonists)antagonists)

PhentolaminePhentolamine

N

NCH3

HO

N CH2

HPharmacological effectsPharmacological effects

(1) Vasodilatation(1) Vasodilatation Blocking Blocking 1 receptor: 1 receptor: vasodilation in both arteriolar resistance vessels and veins(2) Cardiac Stimulation (2) Cardiac Stimulation ReflexReflex ；； blocking blocking 2 receptor 2 receptor ～～ NE release NE release (3) Cholinergic and histamine-like effects(3) Cholinergic and histamine-like effects Contraction of GI smooth muscles,Contraction of GI smooth muscles, Gastric acid secretion Gastric acid secretion

Clinical usesClinical uses

(1) (1) • Hypertension from pheochromocytomaHypertension from pheochromocytoma (sh (short term use). ort term use).

• pre- and post-operation of pheochromocytopre- and post-operation of pheochromocytomama

• Diagnostic test for pheochromocytomaDiagnostic test for pheochromocytoma

(2) Peripheral vascular diseases(2) Peripheral vascular diseases• Acrocyanosis, Raynaud’s diseaseAcrocyanosis, Raynaud’s disease(3) Local vasoconstrictor extravasation(3) Local vasoconstrictor extravasation

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

PhentolaminePhentolamine

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

PhenoxybenzaminePhenoxybenzamine(( 酚苄明）酚苄明）

1 1 receptor antagonistsreceptor antagonists

• prazosinprazosin （哌唑嗪）（哌唑嗪） treatment for hypertensiontreatment for hypertension

22 receptor antagonists receptor antagonists

• yohimbineyohimbine （育亨宾）（育亨宾） for research use onlyfor research use only

ADMEADME

• First-pass elimination,First-pass elimination,• lower bioavailability: propranolollower bioavailability: propranolol

• Hepatic metabolism and renal excretion, Hepatic metabolism and renal excretion, hepatic and renal functions alter the effechepatic and renal functions alter the effects of the drugs and result in large individuts of the drugs and result in large individual variational variation

• So, So, dose individualizationdose individualization is necessary. is necessary.

receptor antagonistsreceptor antagonists

Effects of an AR Antagonist

Pharmacological effectsPharmacological effects

(1) (1) receptor blockade receptor blockade

A. Cardiovascular effectsA. Cardiovascular effects ：：• Depressing heart: Depressing heart: reduction in HR, A-V coreduction in HR, A-V co

nduction, automaticity, cardiac output, oxygnduction, automaticity, cardiac output, oxygen consumptionen consumption

• Hypotension:Hypotension: peripheral blood flow peripheral blood flow , hyp, hypotensive effects in hypertensive patientsotensive effects in hypertensive patients


(1) (1) receptor blockade receptor blockadeB. Bronchial smooth musclesB. Bronchial smooth muscles• induces bronchial smooth muscle contraction iinduces bronchial smooth muscle contraction i

n asthmatic patientsn asthmatic patients

C. MetabolismC. Metabolism• lipolysis lipolysis , glycogenolysis , glycogenolysis , potentiating insuli , potentiating insuli

n effects ~ hypoglycemian effects ~ hypoglycemia

D. Renin secretionD. Renin secretion• decreasing secretion of renindecreasing secretion of renin


(2) Intrinsic sympathomimetic effects(2) Intrinsic sympathomimetic effects• Partial agonists: e.g. Partial agonists: e.g. pindolol （吲哚洛尔） ,, ace

butolol ( 醋丁洛尔 )

(3) Membrane-stabilizing effects(3) Membrane-stabilizing effects• Larger doses of some drugs: quinidine-like effeLarger doses of some drugs: quinidine-like effe

cts, Nacts, Na++ channel block channel block

(4) Others(4) Others• Lowering intraocular pressure;Lowering intraocular pressure;• Inhibiting platelet aggregationInhibiting platelet aggregation


Circulation of Aqueous humorCirculation of Aqueous humor

Clinical usesClinical uses(1) Arrhythmia(1) Arrhythmia ：： supraventricular, sympathetic supraventricular, sympathetic

activity activity

(2) Hypertension(2) Hypertension

(3) Angina pectoris and myocardial infarction(3) Angina pectoris and myocardial infarction

(4) Chronic heart failure(4) Chronic heart failure

(5) Others: (5) Others: hyperthyroidism, migraine headache,hyperthyroidism, migraine headache, glaucoma glaucoma （（ timololtimolol ）） ......


Adverse effectsAdverse effects(1) Heart depression: (1) Heart depression: contraindicated in heart faicontraindicated in heart fai

lure, severe A-V block, sinus bradycardialure, severe A-V block, sinus bradycardia

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

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

(4) Worsening of peripheral vascular constrictio(4) Worsening of peripheral vascular constrictionn

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


• 11, , 2 2 receptor blocking receptor blocking

• no intrinsic activityno intrinsic activity

• first-elimination after oral first-elimination after oral administration, individual variation of administration, individual variation of bioavailabilitybioavailability

PropranololPropranolol

Timolol Timolol (( 噻吗洛尔 )• For treatment of glaucoma (wide-angle)For treatment of glaucoma (wide-angle)

11receptor antagonists, no intrinsireceptor antagonists, no intrinsi

c activityc activity•

• atenolol atenolol : longer t: longer t1/21/2, once daily, once daily

• usually used for treatment of hypeusually used for treatment of hypertensionrtension

Atenolol, MetoprololAtenolol, Metoprolol

α, α, receptor antagonists receptor antagonists

• α, β receptor blocking, β> αα, β receptor blocking, β> α

• usually used for treatment of usually used for treatment of hypertensionhypertension

Labetalol Labetalol (( 拉贝洛尔 )

summary

Agonist Receptorspecificity

Therapeutic uses

epinephrine 1,21,2

• Acute asthma,• anaphylactic 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

specificityTherapeutic uses

ephedrine CNS

•asthma•as a nasal decongestant

Metaraminol •Shock•hypotension

Phenylephrine •supraventricular tachycardia •glaucoma•as a nasal decongestant

Methoxamien •supraventricular tachycardia

Clonidine •hypertension

SalbutemolTerbutalineRitodrinealbuterol

•Asthma•Premature labor

summaryAntagonist Receptor

specificityTherapeutic uses

PhentolaminePhenoxyben

z-amine

• pheochromocytoma• Peripheral vascular diseases• Local vasoconstrictor extravasa

tion

prazosin • hypertension

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

timolol • Glaucoma • hypertension

AtenololMetoprolol

• hypertension

labetalol • hypertension

Local Anesthetics

可卡因

普鲁卡因

丁卡因

苯佐卡因

利多卡因

甲哌卡因

布比卡因

布比卡因

依替卡因

丙胺卡因

Local Anesthetics (LAs)

• Reversibly block nerve conduction• Act on every type of nerve fiber

non/thin myelinated sensory fibers

myelinated sensory fibers

autonomic fibers

motor fibers• Also act on cardiac muscle, skeletal muscle

and the brain• No structural damage to the nerve cell

Action site: voltage-gated Na+ channels

Actions of LAs• Ionic gradient and resting membrane poten

tial are unchanged

• LAs only bind in the inactive state

• Decrease the amplitude of the action potential

• Slow the rate of depolarization

• Increase the firing threshold

• Slow impulse conduction

• Prolong the refractory period

Use-dependent Blockade

Types of local anesthesia

Topical local (surface) anesthesia: for eye, ear, nose, and throat procedures and for cosmetic surgery

Infiltration anesthesia: local injection around the region to be operated.

Conduction anesthesia: local injection around the peripheral nerve trunk

Epidural ansthesia: local injection into the epidural space

Subarachnoid anesthesia or Spinal anesthesia: local injection into the cerebrospinal fluid in subarachnoid cavity

Pharmacokinetics

• LAs bind in the blood to 1-glycoprotein and albumin

• There is considerable first-pass uptake of LAs by the liver

• LAs enter the blood stream by:– Direct injection– Absorption

• Epinephrine decreases this via vasoconstriction• Peak concentrations vary by site of injection

Distribution of LAs

• Alpha phase – rapidly redistributed to well-perfused tissues

• Beta phase – distribution to less perfused or slowly equiliibrating tissues

• Gamma phase – clearance representing metabolism and excretion

Metabolism of LAs

• Esters (rapid)– Hydrolyzed in the plasma by pseudocholinester

ase• Break down product – para-aminobenzoic acid

• Amides (slower)– Occurs in the endoplasmic reticulum of hepatoc

ytes• Tertiary amines are metabolized into secondary ami

nes that are then hydrolyzed by amidases

Allergic Reactions

• Metabolite of “ester” LAs

– Para-aminobenzoic acid

– Allergen

• Allergy to “amide” LAs is extremely rare

CNS Toxicity

• Correlation between potency and seizure threshold– Bupivacaine

• 2 ug/ml

– Lidocaine• 10 ug/ml

Cardiovascular Toxicity• Attributable to their direct effect on cardiac m

uscle

• Contractility

– Negative inotropic effect that is dose-related and correlates with potency

– Interference with calcium signaling mechanisms

• Automaticity

– Negative chronotropic effect

• Rhythmicity and Conductivity– Ventricular arrhythmias

Lidocaine

• One of the most widely used local anesthetics

• Rapid onset, medium duration

• Also available in ointment, jelly, and aerosol

• Other uses: anti-arrhythmic

Eutectic Mixture of Local Anesthetic (EMLA)

• Contains lidocaine, prilocaine, emulsifier, thickener, distilled water

• Must be applied one hour prior to procedure

Pharmacology of General Anesthetics

WHAT IS ANESTHESIA ?

• Definition – “induced, reversible insensibility to surgical stimulation”

• Anesthesia is necessary for some diagnostic, therapeutic, and surgical intervention

• Anesthetics are a class of drugs that produce anesthesia, not all induce unconsciousness

• Some administered as gases or “vapors”, others can be given intravenously

Inhaled anesthetics: mechanism of action

• Many different, apparently unrelated molecules produce general anesthesia – inert gases, simple inorganic & organic compounds, more complex organic compounds

• Characteristics – rapid onset, rapid reversibility, relationship between lipid solubility & potency

Site of action

• Probably on synaptic transmission

• Do they act at one site (unitary hypothesis) or at multiple sites ?

• Do they act via the biochemical milieu or, like many other drugs, at protein receptors ?

Nitrous Oxide

N NO

This anesthetic is a gas at room temperature

DesfluraneC C

F

F

F O

H

C

F

F

H

F

IsofluraneC C

ClF

F

F O

H

C

F

F

H

HalothaneC C H

Cl

Br

F

F

F

C C O

H

C

H

CH

H

H H

H H

H

H Diethyl Ether

Volatile liquids at room temperature

Inhaled anesthetic delivery system

Vaporizing the anesthetic liquid

Gas flowmeters

Mask

Intravenous AnestheticsUsually activate GABAA receptors

Induction of anesthesia

• Higher blood solubility is shown as a larger blood box• Higher solubility means gas rapidly moves into blood, but

concentration that reaches brain increases more slowly

Blood:gas partition coefficient:an index for solubility

Induction of iv anesthetics

Commonly used for initial inductionalong with inhalation anesthetics

MAC –minimum alveolar anesthetic concentration

MAC: The median concentration that results in immobility in 50% of patients

Addition of MAC

Factors that alter MAC• Increase MAC – Being young, hyperthermia,

chronic ETOH, CNS stimulants, hyperthyroidism

• Decrease MAC – Old age, hypothermia, acute ETOH, CNS depressant drugs including narcotics & benzodiazepines

General characteristics

• Analgesia – weak except for nitrous oxide

• Potency – high, except for nitrous oxide

• Muscle Relaxation – some, but weak

• Airway irritation – desflurane worst, sevoflurane best tolerated

• Primary effect on conductive tissue – inhibitory

• Primary effect on smooth muscle – relaxation

• Primary effect on macrophages -- inhibitory

Effects on brain

• Transition to unconsciousness 0.4 MAC O2 consumption but Cerebral Blood Flow means potential injury

with brain tumors/head injury (↑ pressure)

Effects on ventilation

Respiratory Rate; Tidal Volume

Ventilation; PaCO2; Hypoxia Risk

Liver toxicity

• “Halothane Hepatitis”

• Incidence post Halothane – 0.003%

• Symptoms – fever, anorexia, nausea & vomiting that occur 2 - 5 days post-op

• Blood – eosinophilia; altered liver function

• Rare – liver failure & death

Malignant hyperthermia

• Hypermetabolic syndrome – hyperthermia, CO2, tachycardia, cyanosis, muscle rigidity

• Triggered by halogenated anesthetics & depolarizing muscle relaxants

• Familial relationship, i.e. genetic heterogeneity– mutation in Ca2+ reuptake

• Incidence, ~ 1/14,000 anesthesia (0.01%)

• Specific Treatment – Dantrolene (inhibit Ca2+ release from the sarcoplasmic reticulum)

Nitrous oxide toxicity• Bone Marrow Depression – megaloblastic,

inhibition of B12 dependant enzymes

• Peripheral neuropathy

• Expansion of closed air spaces – bowel obstruction, pneumothorax, bullous emphysema, middle ear obstruction, pneumocephalus

• CNS injury – adults & neonates

NITROUS OXIDE KILLS NEURONS IN THE YOUNG AND THE OLD

• Developing rat brain

• Exposure to a combination including nitrous, isoflurane & midazolam

• Persistent learning deficits

Early apoptosisEarly apoptosis

Late apoptosisLate apoptosis

control

exposed

Stages of anesthesia (ether)

• Stage I: analgesia – sensory block in spinal cord

• Stage II: paradoxical excitation due to loss of some inhibitory tone and direct stimulation of excitatory transmission

• Stage III: surgical anesthesia – block of the ascending reticular activating system

• Stage IV: failure – cardiovascular and respiratory collapse due to inhibition

Signs for anesthetic depth

• Tachycardia• Hypertension• Eyelid reflex• Lacrimation• Swallowing• Laryngospasm• Movement

TOO LIGHT TOO DEEP

• Hypotension• Organ failure

Antipyretic-Analgesic and Antiinfl

ammatory Drugs

A.A. General Pharmacological General Pharmacological propertiesproperties

• 1. 1. Inhibition of prostaglandin synthesisInhibition of prostaglandin synthesis

• inhibitinginhibiting cyclooxygenase cyclooxygenase (COX(COX ，环氧酶，环氧酶 ), ),

• decreasing the synthesis of PGs and TXAdecreasing the synthesis of PGs and TXA22, ,

• resulting antipyretic, analgesic, and anti-inflresulting antipyretic, analgesic, and anti-inflammatory effectsammatory effects

• non-steroidal anti-inflammatory drugs (NSAInon-steroidal anti-inflammatory drugs (NSAIDs, Ds, 非甾体抗炎药非甾体抗炎药）。）。

• 2. 2. Antipyretic effectsAntipyretic effects

• Inhibition of PGEInhibition of PGE22 production in the hypot production in the hypot

halamus induced by endogenous pyregehalamus induced by endogenous pyregens after pathological stimuli ns after pathological stimuli temperat temperature ure

• notes:notes: symptomatic control only, not be indicsymptomatic control only, not be indicated in all patients with fever.ated in all patients with fever.

• The effect on body temperature is different frThe effect on body temperature is different from that of chlorpromazine.om that of chlorpromazine.


解热镇痛药氯丙嗪作用机制抑制前列腺素合成，使

散热增加而解热抑制下丘脑体温调节中枢，使其调节功能减弱，不能随外界温度变化而调节体温

作用只能使升高的体温降到正常

氯丙嗪配合物理降温，不仅可使升高的体温降到正常，也可使正常体温降到正常以下

用途用于各种发热用于低温麻醉、人工冬眠不良反应胃肠道反应等锥体外系统反应等

Comparison of properties of two types of drugsComparison of properties of two types of drugs

• 3. 3. Analgesic effectsAnalgesic effects

• Analgesic effect is resulted from inhibition of Analgesic effect is resulted from inhibition of PGEPGE2 2 production. production.

• Effective on the pain of low to moderate intensEffective on the pain of low to moderate intensity related to inflammatory responses.ity related to inflammatory responses.

• PGEPGE22:: a pain stimulant and hyperalgesic agent a pain stimulant and hyperalgesic agent

• The analgesic effect is different from opioid anThe analgesic effect is different from opioid analgesics.algesics.


解热镇痛药阿片类镇痛药作用抑制前列腺素合成起效；

对慢性钝痛有效，对剧烈疼痛或内脏绞痛无效

兴奋阿片受体起效；对各种疼痛均有效

用途头痛、牙痛、神经痛、肌肉或关节痛、痛经等

用于其他药物无效的急性锐痛，晚期肿瘤的剧烈疼痛

不良反应胃肠道反应等，但无成瘾性

有成瘾性


• 4. 4. Anti-inflammatory effectsAnti-inflammatory effects

• PGs induce inflammatory responses.PGs induce inflammatory responses.• Inhibition of PG production can relieve infInhibition of PG production can relieve inf

lammatory responses, such as congestiolammatory responses, such as congestion, exudation, pain.n, exudation, pain.

• The effect is different from that of glucocThe effect is different from that of glucocorticosteroids.orticosteroids.


非甾体抗炎药糖皮质激素作用抑制前列腺素合成起效；

缓解软组织、骨骼、关节的炎症

抑制炎症细胞、炎症分子，多环节炎症炎症病变

用途风湿性、类风湿性炎症，外伤损伤

可用于多种炎症，作用强

不良反应胃肠道反应等抑制机体防御反应，干扰代谢，不良反应广泛


• 5. 5. COX-1 / COX-2 and selectivity of the druCOX-1 / COX-2 and selectivity of the drugsgs

• COX-1:COX-1: constructive;constructive; involved in physiologic re involved in physiologic regulatory functions in GI tract, kidney, gulatory functions in GI tract, kidney, etc.etc.; ;

• inhibition of COX-1 is related to the adverse effinhibition of COX-1 is related to the adverse effects.ects.

• COX-2:COX-2: inducible;inducible; involved in pathological resp involved in pathological responses such as inflammation, and pregnancy; onses such as inflammation, and pregnancy;

• inhibition of COX-2 is related to the therapeutiinhibition of COX-2 is related to the therapeutic effects.c effects.


（－）（＋）

（＋）

（－）

B.B. Salicylates Salicylates

Aspirin Aspirin 阿司匹林阿司匹林Acetylsalicylic acid Acetylsalicylic acid 乙酰水杨酸乙酰水杨酸

CH3

COOH

O C

O

COOH

OH

COONa

OHAspirin Aspirin

阿司匹林阿司匹林

Salicylic acidSalicylic acid

水杨酸水杨酸

Salicylic sodiumSalicylic sodium

水杨酸钠水杨酸钠

• Aspirin Aspirin 阿司匹林阿司匹林

• 1. 1. ADMEADME

• transformed to salicylic acid form in the bodytransformed to salicylic acid form in the body• hepatic metabolism is primarily conjugation.hepatic metabolism is primarily conjugation.• excretion from urine, the excretion of unchanged fexcretion from urine, the excretion of unchanged f

orms of aspirin is increased in the alkalinized urinorms of aspirin is increased in the alkalinized urine.e.

• larger doses ( > 1g/d):larger doses ( > 1g/d): non-linear eliminationnon-linear elimination, zero , zero order kinetic process, easier to accumulation and iorder kinetic process, easier to accumulation and intoxication.ntoxication.


• 2. 2. Pharmacological effects and clinical usPharmacological effects and clinical useses

• (1) Antipyretic, analgesic and anti-inflam(1) Antipyretic, analgesic and anti-inflammatory effectsmatory effects

• moderate doses (0.3moderate doses (0.3 ～～ 0.6 g):0.6 g): antipyretic and analge antipyretic and analgesic effectssic effects

• larger doses (3larger doses (3 ～～ 5 g/d):5 g/d): anti-inflammatory and anti-r anti-inflammatory and anti-rheumatic effects; only relieves symptoms. heumatic effects; only relieves symptoms.

• to treat acute rheumatic fever(to treat acute rheumatic fever( 急性风湿热急性风湿热 ), ), • to abate pain and symptoms of rheumatic & rheumatto abate pain and symptoms of rheumatic & rheumat

oid arthritis (oid arthritis ( 风湿性和类风湿性关节炎风湿性和类风湿性关节炎 ).).


• (2) Inhibition of platelet aggregation(2) Inhibition of platelet aggregation

• small doses (30small doses (30 ～～ 100 mg/d):100 mg/d): inhibiting TXA inhibiting TXA22

synthesis, preventing thrombosis.synthesis, preventing thrombosis.• used to treat ischemic heart disease, reduce used to treat ischemic heart disease, reduce

the mortality of myocardiac infarction, and prevethe mortality of myocardiac infarction, and prevent cerebral thrombosis.nt cerebral thrombosis.

• larger doses:larger doses: inhibiting PGI inhibiting PGI22 synthesis, pro synthesis, pro

moting thrombosis.moting thrombosis.

• PGIPGI22:: vasodilation and platelet depolymerizat vasodilation and platelet depolymerizat

ion (ion ( 血小板解聚血小板解聚 ).).


The mechanism of The mechanism of aspirin:aspirin:

Target enzymes Target enzymes acetylatedacetylated

• 3. 3. Adverse effectsAdverse effects

• (1) GI reactions(1) GI reactions

• stimulating gastric mucosa and CTZ (larger stimulating gastric mucosa and CTZ (larger doses);doses);

• inhibiting PG synthesis in GI tractinhibiting PG synthesis in GI tract

• irritant symptoms; gastric bleeding; irritant symptoms; gastric bleeding; ulcerous disordersulcerous disorders

Contraindications: Contraindications: ulcerous disordersulcerous disorders


• (2) Prolongation of bleeding time(2) Prolongation of bleeding time

• small doses:small doses: inhibiting platelet aggregation inhibiting platelet aggregation

• larger doses:larger doses: inhibiting synthesis of thromboge inhibiting synthesis of thrombogenn

Contraindications: Contraindications: one week prior to surgery; one week prior to surgery; severe hepatic damage; severe hepatic damage; vitamin K deficiency,;vitamin K deficiency,; prothrombinopenia (prothrombinopenia ( 凝血酶原减少症凝血酶原减少症 ).).


• (3) Allergic reactions(3) Allergic reactions

• urticaria(urticaria( 荨麻疹荨麻疹 ), ), • angioneurotic edema, angioneurotic edema, • aspirin-induced asthma,aspirin-induced asthma,• occasionally anaphylactic shock.occasionally anaphylactic shock.

• Contraindications:Contraindications: bronchial asthmabronchial asthma


Aspirin-induced asthma:Aspirin-induced asthma:

Phospholipids of cell menbranePhospholipids of cell menbrane AspirinAspirin Phospholipase APhospholipase A2 2 ((PLAPLA

22))

(-) (-) Arachidonic acidArachidonic acid

Cyclooxygenase Cyclooxygenase LipoxygenenaseLipoxygenenase

(( 环氧酶环氧酶 ) ) PGH PGH2 2 5-HPETE 5-HPETE (( 脂氧酶脂氧酶 ))

↓↓Prostaglandins (PGs)Prostaglandins (PGs) ↑Leukotrienes (LT↑Leukotrienes (LTs)s)

(( 前列腺素前列腺素 )) (( 白三烯白三烯 ))

• (4) Salicylism(4) Salicylism•

dose > 5g/d:dose > 5g/d: CNS symptoms, including CNS symptoms, including mental confusion; hyperventilation.mental confusion; hyperventilation.

i.v.i.v. NaHCO NaHCO33 can promote the excretion of can promote the excretion of aspirin.aspirin.

•

• (5) Hepatic damage (5) Hepatic damage

• Overdose: Overdose: hepatic damage hepatic damage Reye’s syndrome(Reye’s syndrome( 瑞夷综合征瑞夷综合征 ):): in childre in childre

n, severe hepatic damage (n, severe hepatic damage ( 严重的肝损害严重的肝损害 ) an) and encephalopathy (d encephalopathy ( 脑病脑病 ))


Dose-response Dose-response relationship of relationship of aspirin:aspirin:

therapeutic effects; therapeutic effects; adverse effectsadverse effects

4. 4. Drug interactionsDrug interactions


C.C. Para-aminophenol Para-aminophenol derivativesderivatives

Acetaminophen Acetaminophen 对乙酰氨基酚对乙酰氨基酚

ParacetamolParacetamol 扑热息痛扑热息痛NHCOCH3

OH

• Acetaminophen Acetaminophen （对乙酰氨基酚）：（对乙酰氨基酚）：

• antipyretic and analgesic effects are mantipyretic and analgesic effects are mild and lasting, ild and lasting, but almost no anti-inflambut almost no anti-inflammatory effects, matory effects, - not a- not a NSAIDNSAID

• higher selectivity to COX in CNS. higher selectivity to COX in CNS.

mainly used in cold, fever, and headacmainly used in cold, fever, and headache, he, etcetc..

overdose can damage liver and kidney.overdose can damage liver and kidney.

C.C. Para-aminophenol Para-aminophenol derivativesderivatives

Differences between NDifferences between NSAIDs and AcetaminoSAIDs and Acetamino

phenphen

Toxic metabolites of Toxic metabolites of acetaminophenacetaminophen

D.D. Other anti-inflammatory Other anti-inflammatory drugsdrugs

Salicylates:Salicylates: aspirin aspirin

Para-aminophenol derivatives:Para-aminophenol derivatives: acetaminophen acetaminophen

Indole and indene acetic acid derivatives:Indole and indene acetic acid derivatives:

indomethacin, sulindacindomethacin, sulindac

Propionic acid derivatives:Propionic acid derivatives:

ibuprofen, naproxen, fenopofen, ketoprofenibuprofen, naproxen, fenopofen, ketoprofen

COX-2 selective inhibitors:COX-2 selective inhibitors: meloxicam, celecoxide, rofenxid meloxicam, celecoxide, rofenxid

Others:Others: phenylbutazone, diclofenac phenylbutazone, diclofenac

N

CH2CH3CO

C

O

Cl

CH3

OH

O

CH3

CHCOOH

CH3

CH2CH

CH3

NS

N

CONH

O O

CH3

OH

indomethacinindomethacin

吲哚美辛吲哚美辛

piloxicampiloxicam

吡罗昔康吡罗昔康

ibuprofenibuprofen

布洛芬布洛芬

D.D. Other anti-inflammatory Other anti-inflammatory drugsdrugs

• indomethacin indomethacin 吲哚美辛：吲哚美辛： stronger efficacy, stronger efficacy, controlling special types of fever; severe advercontrolling special types of fever; severe adverse effectsse effects

• ibuprofen ibuprofen 布洛芬布洛芬（芬必得）（芬必得）：： stronger antstronger ant

ipyretic, analgesic and anti-inflammatoryipyretic, analgesic and anti-inflammatory effecteffects; weaker GI reactions; vision damages; weaker GI reactions; vision damage

• piloxicam piloxicam 吡罗昔康吡罗昔康 :: long-acting anti-inflamlong-acting anti-inflammatory and analgesic agent; long-term use indmatory and analgesic agent; long-term use induces hemorrhage and ulcers in GI tractuces hemorrhage and ulcers in GI tract

COX-2 selective anti-inflammatory COX-2 selective anti-inflammatory drugsdrugs

Meloxicam Meloxicam 美洛昔康美洛昔康

stronger effect on COX-2 than COX-1stronger effect on COX-2 than COX-1

long-acting (tlong-acting (t1/21/2 20 h) 20 h)

weaker GI reactions weaker GI reactions

Documents

Drugs affecting peripheral nervous system San-Hua Fang, PhD 方三华 Dept. of Pharmacology, School of Medicine, Zhejiang University [email protected]