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Antipyretic, Analgesic, and Anti-inflammatory Drugs
(Non-steroidal anti-inflammatory drugs, NSAIDs)
Arachidonic acid
Phospholipase A2
Corticosteroids ⊕ BradykininAngiotensin
Cyclooxygenase (COX)
PGG2Prostacyclin(PGI2)
PGE2
PGF2α
Thromboxane A2 Dipyridamole
hydroperoxidase
NSAIDs
Leukotrienes
5-lipoxygenase
Phospholipid
PGH2
TXA synthase
花生四烯酸
COX-1 COX-2
Synthesis intrinsic induced
Functions physiological:
gastrointestinal protection
platelet aggregation regulation
vascular resistance regulation
renal blood flow regulation
physiological: production of PG elevated during pregnancy
pathological:
producing proteinase, PG, and other inflammatory mediators
Characteristics comparison between COX-1 and COX-2
抑制 COX-2抑制 COX-2
抑制 COX-1抑制 COX-1
解热、镇痛、抗炎
胃黏膜损害、出血
损害肾脏
Aspirin and other salicylates (阿司匹林及水杨酸类)
Aniline derivatives (苯胺类衍生物)
Indole derivatives (吲哚类衍生物)
Propionic acid derivatives (丙酸类衍生物)
Others ( 烯醇酸类,灭酸类,杂环芳基乙酸类,茚乙酸类,吡唑酮类,以及选择性 COX-2 抑制剂 )
Classification of NSAIDs :
The mechanism of aspirin: acetylating COX enzyme irreversibly
1. Aspirin
1.1 Actions and therapeutic uses:
A Antipyretic and analgesic actions:
-- resets the thermostat toward normal and lowers
the body temperature by increasing heat dissipation;
-- alleviates pain of low to moderate intensity arising
from integument, especially with inflammation.
1. Aspirin
感染原和细菌内毒素等外源性致热原
机 体
体温升高(发热)
体温调节中枢
内热原(细胞因子 IL-1、 IL-6、 TNF等)
中枢 PG的合成增加 解热镇痛药解热镇痛药(—)
氯丙嗪
效应 抑制体温调节 解热
作用机制 抑制体温调节中枢 抑制环加氧酶抑制 PGs的合成和释
放特点 1 .环境温度低——降温环境温度越低,降温越显著可降发热、正常体温2 .高温环境——升温
只降发热体温不降正常体温
用途 人工冬眠疗法(降温) 治疗发热
解热镇痛药与氯丙嗪降温作用比较
NSAIDs
解热镇痛药与阿片类镇痛药镇痛作用比较 阿片类镇痛药 解热镇痛药
作用部位 中枢 外周(主)
作用机制 激动阿片受体 抑制环氧酶,使 PG合成减少
镇痛特点 强大,伴有镇静作用及欣快感
中等强度,无镇静作用及欣快感
适应证 用其他药无效的急性锐痛 慢性钝痛
不良反应 易成瘾,抑制呼吸 无成瘾性及呼吸抑制
1.1 Actions and therapeutic uses:
B Anti-rheumatic actions: at large dose (4-6 g/d).
C Anti-aggregation of platelets and
vasoconstriction: at small dose (~100 mg/d),
irreversibly inhibits thromboxane production in
platelets without markedly affecting PGI2 in the
endothelial cells of the blood vessel.
1. Aspirin
1.2 Adverse effects:
Gastrointestinal effects: epigastric distress, nausea
and vomiting, bleeding, ulcer (long term use).
Allergic effects:
Urticaria (风疹)Bronchoconstriction (aspirin asthma) angioneurotic edema
1. Aspirin
1.2 Adverse effects:
Prolonged bleeding time
Excessive ventilation: respiratory alkalosis
Salicylism ( 水杨酸反应 ) : toxicity in the CNS (headache, dizziness, nausea, vomiting, tinnitus)
Reye’s syndrome: liver and brain injury in children with virus infection
1. Aspirin
2. Acetaminophen (对乙酰氨基酚) Slow and prolonged antipyretic and
analgesic effects No obvious anti-inflammation effect Less stimulation to gastrointestinal tract Damage of liver and kidney if used for a
long time and at high dose
3. Propionic acid derivatives (丙酸类)
Includes ibuprofen ( 布洛芬 ), naproxen ( 萘普生 ), etc Anti-inflammatory, analgesic and antipyretic activity Less gastrointestinal effects Change platelet function and prolong bleeding time Used for the treatment of various arthritis and
dysmenorrhea ( 痛经 )
4. Indomethacin (吲哚美辛)
One of the most potent inhibitors of COX High potency of anti-inflammatory, analgesic, and
antipyretic activity Used for ankylosing spondylitis ( 强直性脊柱炎
AS) , Osteoarthritis ( 骨关节炎 OA) and gout ( 痛风 ) Effective in treating patent ductus arteriosus (动脉导
管未闭)
High incidence of adverse effects like:
central nervous system effect
gastrointestinal complaints
allergic reactions
hematopoietic reactions
Sulindac ( 舒林酸 ) and Etodolac ( 依托度酸 ) are less toxic and used for OA, RA, AS and acute gout.
4. Indomethacin
5. Selective COX-2 inhibitors
Less incidence of gastrointestinal upset
(peptic ulceration, bleeding)
Related to an increase in the risk for heart attack, thrombosis and stroke.
Include celecoxib ( 塞来昔布 ), refecoxib ( 罗非昔布 ), nimesulide ( 尼美舒利 ), etc
6. Inhibitors of TNF-
TNF- is the predominant factor in inflammatory reaction.
Include etanercept ( 依那西普 ), infliximab ( 英夫利西单抗 ), adalimumab ( 阿达木单抗 )
Used for the treatment of RA, AS and other autoimmune diseases.
General anesthetics and barbiturates for anesthesia ( 麻醉 )
Local anesthetics and opioids for both anesthesia and analgesia ( 镇痛 )
Clinical relief of acute pain
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
Anesthetics
General anesthetics: Some administered as gases or “vapors”, others can be given intravenously
Local anesthetics: local application
Before October 16, 1846 "Suffering so great as I underwent cannot be
expressed in words . . . but the blank whirlwind of emotion, the horror of great darkness, and the sense of desertion by God and man, which swept through my mind, and overwhelmed my heart, I can never forget.”
-Ashhurst J Jr , Surgery before the days of anesthesia, 1997
http://content.nejm.org/cgi/reprint/348/21/2110.pdf
On October 16, 1846, William Morton, a dentist at Massachusetts General Hospital, employed ether in the surgical removal of a tumor
with no signs or reports of pain in the patient.
History 1846, Ether 1860, Cocaine 1884, N2O 1905, Procaine 1934, Thiopental 1943, Lidocaine ……
Pharmacology of Local Anesthetics (LAs)
Local Anesthetics (LAs) Reversibly block nerve conduction Act on every type of nerve fibers:
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
可卡因
普鲁卡因
丁卡因
苯佐卡因
酯类
利多卡因
甲哌卡因
布比卡因
依替卡因
丙胺卡因
酰胺类
Action site: voltage-gated Na+ channels
Actions of LAs Ionic gradient and resting membrane
potential are unchanged Only bind in the inactivated state: use
dependent Decrease the amplitude of the action
potential Slow the rate of depolarization Increase the firing threshold Slow impulse conduction Prolong the refractory period
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 anesthesia: local injection into the epidural space
Subarachnoid anesthesia or Spinal anesthesia: local injection into the cerebrospinal fluid in subarachnoid cavity
Infiltration anesthesia
Conduction anesthesia(cervical plexus)
Pharmacokinetics
LAs bind in the blood to a1-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
Metabolism of LAs
Esters (rapid) Hydrolyzed in the plasma by
pseudocholinesterase Break down product – para-aminobenzoic acid
( 对苯氨甲酸 )
Amides (slower) Occurs in the endoplasmic reticulum of
hepatocytes Tertiary amines are metabolized into
secondary amines 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
muscle
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
Comparison of LAsPotency Toxicity Permeability Application
Procaine Weak Low (allergic)
Weak Not for topical, skin test
Tetracaine Strong High Strong Especially topical ,Not for infiltration
Lidocaine Strong Low Strong All kinds
Ropivacaine Strong Low Strong Epidural and conduction
Pharmacology of General Anesthetics
General Anesthetics General anesthesia: analgesia, amnesia, loss
of consciousness, inhibition of sensory and autonomic reflexes, and skeletal muscle relaxation.
Intravenous anesthetics (barbiturates, etc) Inhaled anesthetics (gases, or volatile
liquids)
Intravenous Anesthetics
Usually activate GABAA receptors, or block NMDA receptors
硫喷妥钠
咪达唑仑
丙泊酚
依托咪酯 氯胺酮
Induction of iv anesthesia
Commonly used for initial anesthesia inductionalong with inhalation anesthetics
Inhaled anesthetics Many different, apparently unrelated
molecules produce general anesthesia
– innert gases, simple inorganic & organic compounds, more complex organic compounds
Characteristics – rapid onset (emergence), rapid reversibility, relationship between lipid solubility & potency
Stages of anesthesia (ether)
Stage I: analgesia – sensory block in spinal cord, and later amnesia
Stage II: paradoxical excitation (irregular breath, retching, vomiting, struggle) 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 流泪 Swallowing Laryngospasm 喉痉
挛 (involuntary spasm of the laryngeal cords
Movement
TOO LIGHT TOO DEEP• Hypotension• Organ failure
Inhaled anesthetic delivery system
Vaporizing the anesthetic liquid
Gas flowmeters
N NO
Nitrous Oxide (N2O)
Laughing gas
Diethyl Ether
Volatile liquids at room temperature
Sevoflurane ( 七氟烷 )Isoflurane
Halothane
Induction of anesthesia
Higher solubility (shown as a larger blood box) means gas rapidly moves into blood, but concentration that reaches brain increases more slowly
Blood:gas partition coefficient(an index for solubility): =[blood]/[alveoli]
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 ( 甲状腺功能亢进 )
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 ventilation
Respiratory Rate; Tidal Volume
Ventilation; PaCO2; Hypoxia Risk
Effects on brain
Transition to unconsciousness 0.4 MAC O2 consumption but Cerebral Blood Flow means potential
injury with brain tumors/head injury (↑ pressure)
Liver toxicity “Halothane Hepatitis”
Incidence post Halothane – 0.003%
Symptoms – fever, anorexia, nausea & vomiting that occur 2 - 5 days post-op
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 ( 气胸 ), bullous emphysema ( 大泡性肺气肿 ), middle ear obstruction, pneumocephalus ( 颅腔积气 )
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