Drugs affecting peripheral nervous system San-Hua Fang, PhD 方三华 Dept. of Pharmacology, School...
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Transcript of Drugs affecting peripheral nervous system San-Hua Fang, PhD 方三华 Dept. of Pharmacology, School...
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
receptor antagonistsreceptor antagonists
(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
receptor antagonistsreceptor antagonists
(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
receptor antagonistsreceptor antagonists
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 )) ......
receptor antagonistsreceptor antagonists
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.
receptor antagonistsreceptor antagonists
• 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.
A.A. General Pharmacological General Pharmacological propertiesproperties
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.
A.A. General Pharmacological General Pharmacological propertiesproperties
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
Comparison of properties of two types of drugsComparison of properties of two types of drugs
• 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.
A.A. General Pharmacological General Pharmacological propertiesproperties
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
Comparison of properties of two types of drugsComparison of properties of two types of drugs
• 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.
A.A. General Pharmacological General Pharmacological propertiesproperties
(-)(+)
(+)
(-)
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.
B.B. Salicylates Salicylates
• 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 ).).
B.B. Salicylates Salicylates
• (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 ).).
B.B. Salicylates Salicylates
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
B.B. Salicylates Salicylates
• (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 ).).
B.B. Salicylates Salicylates
• (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
B.B. Salicylates Salicylates
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 ))
B.B. Salicylates Salicylates
Dose-response Dose-response relationship of relationship of aspirin:aspirin:
therapeutic effects; therapeutic effects; adverse effectsadverse effects
4. 4. Drug interactionsDrug interactions
B.B. Salicylates Salicylates
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