Transcript 2 receptor

Adrenergic Pharmacology
Shi-Hong Zhang (张世红), PhD
Dept. of Pharmacology,
School of Medicine, Zhejiang University
[email protected]
Noradrenergic Nerve:
Synthesis, storage
and release of NE
Tyrosine
tyrosine hydroxylase (TH)
L-DOPA
DOPA decarboxylase
dopamine (DA)
dopamine beta-hydroxylase (DBH)
norepinephrine (NE)
• Uptake
neurotransmitter transporters
– uptake 1: neuronal uptake
– uptake 2: non-neuronal uptake
• Enzymatic degradation
– monoamine oxidase (MAO)
– catechol-O-methyltransferease
(COMT)
Regulation of NE Synthesis and Turnover
Tyrosine hydroxylase (TH) activity is rate limiting
TH activity is inhibited by NE product
TH activity is modulated by presynaptic autoreceptors
- alpha2 receptors can reduce NE release
- beta2 receptors can increase NE release
Presynaptic heteroreceptors can modulate NE
release
- ACh can reduce NE release
Tyrosine hydroxylase activity increases or decreases
to maintain steady-state levels of norepinephrine.
The above processes contribute to regulation of
steady-state NE levels (rate of synthesis = rate of
output)
Catecholamine
Biosynthetic Pathway
Norepinephrine and Epinephrine
Synthesis in the Adrenal Medulla
- PNMT is located in the cytosol
- DBH is located in vesicles
- EPI is stored in vesicles.
- EPI (~80%) and NE (~20%) released into
blood
NE
NE
PNMT
EPI
Chromaffin cell
EPI
NE Metabolism
- takes place within the same cells where the amines are synthesized, and in liver
- Extraneuronal O-methylation of norepinephrine and epinephrine to metanephrines
represent minor pathways of metabolism.
MHPG(3-甲氧4-羟苯乙二醇):
was used as
an index of CNS NE turnover
but generated mostly from
periphery
VMA(香草扁桃酸):
sometimes used as
an index of NE turnover
Sulfate conjugates
also prevalent
or MHPG
Adrenergic Receptor Subtypes & G-Protein
Coupled Mechanisms
1 Adrenergic Receptors:
Phospholipase C activation, IP3 increase through Gq
 mechanism: mobilizes and increases intracellular free
calcium
 effects: primarily smooth muscle contraction
2 Adrenergic Receptors:
Inhibition of adenyl cyclase through Gi proteins
 mechanism: decreases intracellular cAMP levels
 effects: decreased protein phosphorylation, decreased
cellular function
Adrenergic Receptor Subtypes & G-Protein
Coupled Mechanisms
β Adrenergic Receptors:
Activation of adenyl cyclase through Gs proteins
 mechanism: increases intracellular cAMP levels
 effects: phosphorylation of intracellular proteins 
smooth muscle relaxation, cardiac muscle contraction
可乐定
去氧肾上腺素
异丙肾上腺素
q
Four Major Activators of the
Adrenergic System
1 Hypoglycemia
2 Hypothermia
3 Hypoxia
4 Hypotension
•
•
Hypoxia - response is mainly cardiovascular: b1 receptors via
SNS NE increase heart rate & contractility, resulting in
greater cardiac output; b2 receptors via adrenal Epi
vasodilate blood vessels in muscle, increasing oxygen
delivery, and mediate bronchodilation to facilitate oxygen
intake.
Hypoglycemia - response is mainly metabolic, but b2
vasodilation in muscle increases glucose (as well as oxygen)
delivery.
Response to
Hypoglycemia
The release of E
(and to a lesser
extent NE) by the
adrenal is in direct
response to falling
blood glucose
levels
Insulin injection
(insulin injection)
Glycogenolysis
•
•
•
•
The brain and muscle must have glucose
The main sites of glycogenolysis are the
liver and muscle
Glycogen is broken down by glycogen
phosphorylase
This enzyme is activated by both PKA and
PKC through stimulation of b2 and 1
adrenergic receptors, respectively
Gluconeogenesis
•
The liver and kidney are the key sites
•
Substrates: lactate (from muscle) and glycerol
(from fat)
•
Several enzymes in the pathway are activated by
PKC through 1 stimulation
•
Both glycogenolysis & gluconeogenesis are
indirectly stimulated by facilitating release of
glucagon (b2) & inhibiting release of insulin (2)
Lypolysis
•
Lipases are stimulated by b (esp. b3) receptors
Energy Mobilization by Epinephrine
Response to Hypothermia:
1 - Piloerection
2 - Peripheral vasoconstriction
3 - Thermogenesis
-Brown fat
a) activation
b) proliferation
Summary: Adrenoceptors
 receptors
• 1 receptors: vasoconstriction: increased
peripheral resistance, BP↑; contraction of radial
muscle of iris: mydriasis
• 2 receptors: CNS, presynaptic membranes of
adrenergic nerves: vasodilatation, inhibition of NE
release; inhibition of insulin release
Summary: Adrenoceptors
b receptors
• b1 receptors: contractility↑, automaticity↑, conduction↑,
oxygen-consumption↑, cardiac output↑: heart stimulation;
increased lipolysis
• b2 receptors: relaxation of bronchial smooth muscles:
bronchodilation; slight vasodilation; increased muscle and
liver glycogenolysis; increased release of glucagon
• b3 receptors: lipolysis, thermogenesis
Drug classification
1. Direct actions on the receptors
Agonists
Antagonists
2 Indirect actions via affecting transmitters
Synthesis (L-dopa)
Transport and storage (imipramine丙咪嗪, reserpine 利舍
平)
Release (ephedrine 麻黄碱, amphetamine 安非他明)
Inactivation (MAOI)
Drug classification
3. Mimetics and antagonists
(1) Mimetics
direct-acting: receptor agonists
indirect-acting: increasing amounts and/or effects of
transmitters
(2) Antagonists
direct-acting: receptor antagonists
indirect-acting: decreasing amounts and/or effects of
transmitters
Structure-activity relationship of
catecholamines and related compounds
•Strong efficacy
•Short duration
•No entry to CNS
• Receptor activation
苯乙胺
•Resistant to MAO
麻黄碱
Methamphetamine
甲基苯丙胺
• Catecholamine
• Non-catecholamine
苯乙胺
– Indirect-acting by
– High potency in
causing the release of
activating  or b
stored catecholamine.
receptors
– Not inactivated by
COMT; some are poor
– Rapid inactivation by
substrate for MAO
COMT and by MAO
(orally active, a
– Poor penetration into the
prolonged duration of
CNS
action)
– Greater access to the
CNS
Adrenomimetic Agents
• Adrenomimetic; sympathomimetic;
adrenergic agonist
• The mode of action: DIRECT; INDIRECT;
MIXED
• DIRECT: direct interaction with adrenergic
receptors.
• INDIRECT: causes response indirectly by
provoking release of intraneuronal NE into
synaptic cleft or interfering with NE reuptake.
• MIXED: combination of DIRECT and
INDIRECT mechanisms.
Adrenergic agonists
Norepinephrine, Noradrenaline
Pharmacological effect
1, 2 receptor agonists
(1) Vascular effects：
1：vasoconstriction (skin, renal, brain,
hepatic, mesenteric, etc.), blood flow 
2：inhibiting NE release
(2) Blood pressure：
Systolic BP , Diastolic BP (especially at larger doses)
Norepinephrine
(3) Cardiac effects：
weak direct stimulation (b1);
inhibition via reflex (in vivo)
Net result: little cardiac stimulates
Effects of Norepinephrine on BP and HR
Norepinephrine
Clinical uses (limited therapeutic value)
(1) Shock
• used in early phase of neurogenic shock: small doses
and shorter duration
(dopamine is better; replaced by Metaraminol 间羟胺，
αagonist and NE releaser, weaker but longer effect)
(2) Hypotension due to drug poisoning
• especially for chlorpromazine （氯丙嗪）
(3) Hemorrhage in upper alimentary tract
• orally given after dilution
Norepinephrine
Adverse effects
(1) Ischemia and necrosis at the site of iv
administration
- relieved by filtrating the area with phentolamine (酚妥拉明，
 receptor antagonist)
(2) Acute renal failure
- avoiding larger doses and longer duration; monitoring
urinary volume
(3) Contraindication
- hypertension, arteriosclerosis, heart diseases, severe
urinary volume , microcirculation disorders
1 receptor agonists
Phenylephrine (去氧肾上腺素)
Methoxamine (甲氧明)
• Induces reflex bradycardia, used in hypotension
under anesthesia and drug poisoning,
paroxysmal supraventricular tachycardia ；
• Phenylephrine: Mydriasis, pupillary dilator
muscles, no or less effect on intraocular
pressure, short-acting (for several hours);
act as a nasal decongestant (鼻血管收缩药)
2 receptor agonists
• Clonidine:
Uses: antihypertensive drug; can be administered
as transdermal patch (permits continuous
administration)
Mechanism of action:
2 - adrenergic partial agonist; actions
predominantly in CNS
lowers blood pressure by inhibiting sympathetic
vasomotor tone
2 receptor agonists
• Clonidine
Adverse effects: iv administration may result in
transient increase in blood pressure (activation of
post-synaptic receptors); dry mouth, sedation
2 receptor agonists
Oxymetazoline (羟甲唑啉): a nasal decongestant
Apraclonidine (阿可乐定): decreases intraocular
pressure.
Epinephrine, Adrenaline
Pharmacological effects ：  1, 2, b1, b2
receptor agonists
(1) Cardiac effects
b1: contractility  (positive inotropic),
HR  (positive chronotropic),
cardiac output ,
oxygen consumption ,
induces arrhythmia
Epinephrine, Adrenaline
Pharmacological effects ：  1, 2, b1, b2
receptor agonists
(2) Vascular effects
1：vasoconstriction (skin, mucous, viscera),
especially at larger doses
b2：vasodilatation of skeletal muscles
and coronary vessels
Concentration-dependent response in
vascular smooth muscle to epinephrine
Predominant Effects
low [EPI] β2 > α
high [EPI] α > β2
Epinephrine
(3) Blood pressure- two phases
Systolic BP, Diastolic BP↓(slight) , pulse pressure 
Epinephrine
(4) Respiratory
b2：dilatation of bronchial smooth muscles
(Bronchodilatation)
inhibition of degranulation of mast cells
1：reducing congestion and edema of bronchial mucosa
(5) Gastric and bladder smooth muscles: relaxation (b2)
(6) Eye: intraocular pressure ↓ (α2)
(7) Metabolic effects
blood glucose  (b2 and 1,2, hyperglycemia);
free fatty acids  (b, lipolysis)
Epinephrine
Clinical uses
Topical uses:
Systematic uses:
• Adjuvant of
local anesthesia
• Cardiac arrest
• Bleeding
• Glaucoma
• Anaphylactic
shock (过敏性休克)
• Acute bronchial
asthma
Epinephrine
Adverse effects
(1) Cardiac arrhythmias
(2) Hemorrhage (cerebral or subarachnoid) :
reason: a marked elevation of BP
(3) Central excitation: anxiety, headache...
(4) Contraindications: heart diseases,
hypertension, coronary arterial disease,
arteriosclerosis （动脉硬化）, hyperthyroidism （甲
亢）
Ephedrine 麻黄碱
HO
NH
CH
CH
OH
CH3 CH3
HO
Ephedrine
CH
CH
OH
Epinephrine
NH
CH3
CH2
CH
NH
CH3 CH3
Methamphetamine
Properties：
- Promoting release of NE, weak agonist effects on 1、2、
b1、b2 receptors
- chemically stable, orally effective；
- less potent but longer action duration;
- central stimulating: alertness , fatigue ↓, prevents
sleep (adverse effects)
- Tachyphylaxis (快速耐受).
Ephedrine
Clinical uses
(1) Prevention of hypotension: anesthesia
(2) Nasal decongestion: nasal drop
(3) Bronchial asthma: mild, chronic cases
(4) Relieving allergic disorders: urticaria 风疹,
angioneurotic edema 血管神经性水肿
Dopamine
Pharmacological effects:
, b receptor, dopaminergic
receptor agonists
(1) Cardiac effects：b1 receptor,
weak
(2) Vascular effects：
DA receptor: vasodilatation of
renal, mesenteric arteries (small
doses);
1 receptor: vasoconstriction of
skin, mesenteric/renal vessels
(larger doses)
Dopamine
Clinical uses
(1) Shock
cardiac and septic (感染性) shock
(2) Acute renal failure
combined with furosemide
Adverse effects
short-lived; tachycardia, arrhythmia, reduction
in urine flow (renal vasoconstriction)
Isoproterenol, Isoprenaline:
Pharmacological effects:
b1 , b2 receptor agonists, NE releaser
(1) Cardiac effects (b1 receptor)
(2) Vascular effects and blood pressure
b2 receptor: dilatation of skeletal
muscles and coronary vessels；
SP , DP  or , pulse pressure 
(3) Bronchodilatation (b2 receptor)
(4) Metabolism
Promoting effects as epinephrine
Effects of catecholamines（therapeutic doses）
Predominant Effects:
NE :  & b1 effects
EPI : b1, b 2 then at higher concentrations  effects predominate
ISO: b1 and b 2
Isoproterenol
Clinical uses
(1) Cardiac arrest / A-V block: in emergencies
(2) Shock: replaced by other sympathomimetics
(muscular vasodilatation)
(3) Bronchial asthma
Adverse effects
(1) Heart stimulation, arrhythmia
(2) Contraindications: coronary heart disease,
myocarditis （心肌炎）, hyperthyroidism
b1 receptor agonists
Dobutamine （多巴酚丁胺）
• Heart failure (after cardiac surgery or
congestive HF or acute myocardial
infarction; short-term treatment)
• Cardiac stimulation
b2 receptor agonists
Terbutaline (特布他林)
• Uses: Bronchial asthma
dilation of bronchial smooth muscle; b2 > b1 agonist
(partially selective): preferential activation of pulmonary
b2 receptors by inhalation.
Use: Premature Labor (ritodrine).
• Adverse effects:
headache, cardiac stimulation and skeletal muscle fine
tremor (b2 receptors on presynaptic motor terminals; their
activation enhances ACh release).
INDIRECT-acting drugs (summary)
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
Competitive, nonselective
Pharmacological effects
CH 3
N
N
CH 2
N
H
HO
(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 
Phentolamine
Clinical uses
(1) Decrease blood pressure
• Hypertension from pheochromocytoma (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
(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
Pheochromocytoma is a rare catecholaminesecreting 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 & ±b)
Pheochromocytoma
Phenoxybenzamine 酚苄明
• Irreversible, nonselective ( 1 and 2
antagonists )
• Long-acting
• Similar to phentolamine in actions and
clinical uses
1 receptor antagonists
• Prazosin: treatment for hypertension
• Tamsulasin: 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
b receptor antagonists
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.
b receptor antagonists
Pharmacological effects
(1) b receptor blockade
A. Cardiovascular effects：
• Depressing heart: reduction in HR, A-V
conduction, automaticity, cardiac output,
oxygen consumption
• Hypotension: peripheral blood flow ,
hypotensive effects in hypertensive
patients
b receptor antagonists
(1) b receptor blockade
B. 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
b receptor antagonists
(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
Circulation of Aqueous humor
b receptor antagonists
Clinical uses
(1) Arrhythmia: supraventricular, sympathetic
activity 
(2) Hypertension
(3) Angina pectoris and myocardial infarction
(4) Chronic heart failure
(5) Others: hyperthyroidism, migraine headache,
glaucoma (timolol)...
b receptor antagonists
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.
Propranolol
• b1, b2 receptor blocking
• no intrinsic activity
• first-elimination after oral administration,
individual variation of bioavailability
Timolol
• For the treatment of glaucoma (wide-angle)
Atenolol, Metoprolol
• b1receptor antagonists, no intrinsic
activity
•
• atenolol : longer t1/2, once daily
• usually used for the treatment of
hypertension
α, b receptor antagonists
Labetalol
• α, β receptor blocking, β> α
• usually used for treatment of
hypertension
Summary
Agonist
Receptor
specificity
Therapeutic uses
epinephrine
1,2
b1,b2
• Acute asthma,
• Anaphylactic(过敏性) shock,
• in local anesthetics to
increase duration of action
norepinephrine
1,2
(b1)
• shock
isoproterenol
b1,b2
• Asthma
• As cardiac stimulant
dopamine
Dopaminergic
, b
• Shock,
• Congestive heart failure
dobutamine
b1
• Heart failure
Summary
Agonist
Receptor
specificity
Therapeutic uses
Ephedrine(麻黄碱)
, b
•asthma
•as a nasal decongestant
Metaraminol (间羟
胺)

•Shock
•hypotension
Phenylephrine (苯
肾上腺素)
1
•supraventricular tachycardia
•glaucoma
•as a nasal decongestant
Methoxamine (甲
氧胺)
1
•supraventricular tachycardia
Clonidine
2
•hypertension
Salbutemol
Terbutaline
Ritodrine
b2
•Asthma
•Premature labor
Summary
Antagonist
Receptor
specificity
Therapeutic uses
Phentolamine
Phenoxybenzamine (酚苄
明)
1, 2
• pheochromocytoma
• Peripheral vascular diseases
• Local vasoconstrictor
extravasation
prazosin
1
• hypertension
propranolol
b1, b2
•
•
•
•
•
•
timolol
b1, b2
• Glaucoma
• hypertension
Atenolol
Metoprolol
b1
• hypertension
labetalol
, b
• hypertension
Hypertension
Glaucoma
Migraine
Hyperthyroidism
Angina pectoris
Myocardial infarction
Pharmacology for
Pain and Analgesia
What is pain
An unpleasant sensory or emotional experience associated with
actual or potential tissue damage, or described in terms of such
damage. Pain is always subjective. Each individual learns the
application of the word through experiences related to injury in
early life. It is unquestionably a sensation in a part of the body,
but it is also unpleasant, and therefore also an emotional
experience. Many people report pain in the absence of tissue
damage or any likely pathophysiological cause; usually this
happens for psychological reasons. There is no way to distinguish
their experience from that due to tissue damage, if we take this
subjective report.
IASP. Pain 1979(6)249-252
Physiology of Pain
Pain sensation
Acute Pain
- First pain：sharp, pricking, well defined，A fibers
- Second pain：dull, aching, poorly localized, C
fibers
Chronic Pain
- Inflammatory
- Neuropathic
- Diabetic
- Bone cancer pain
- Fibromyalgia
- Migraine
- Psychogenic pain
Milligan et al, 2009
Clinical relief of acute pain
• General anesthetics and barbiturates for
anesthesia (麻醉)
• Local anesthetics and opioids for both
anesthesia and analgesia (镇痛)
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
酯类
可卡因
普鲁卡因
丁卡因
苯佐卡因
酰胺类
利多卡因
甲哌卡因
布比卡因
依替卡因
丙胺卡因
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 LAs
Potency 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
硫喷妥钠
咪达唑仑
丙泊酚
依托咪酯
氯胺酮
Usually activate GABAA receptors, or block NMDA receptors
Induction of iv anesthesia
Commonly used for initial anesthesia induction
along with inhalation anesthetics
Inhaled anesthetics
• Many different, apparently unrelated molecules
produce general anesthesia
– inert 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
TOO LIGHT
•
•
•
•
•
•
Tachycardia
Hypertension
Eyelid reflex
Lacrimation 流泪
Swallowing
Laryngospasm 喉痉挛
(involuntary spasm of
the laryngeal cords
• Movement
TOO DEEP
• Hypotension
• Organ failure
Inhaled anesthetic delivery system
Vaporizing the anesthetic liquid
Gas flowmeters
Nitrous Oxide (N2O)
O
N
N
Laughing gas
Volatile liquids at room temperature
Diethyl Ether
Isoflurane
Halothane
Sevoflurane (七氟烷)
Induction of anesthesia
Blood:gas partition coefficient
(an index for solubility):
=[blood]/[alveoli]
Higher solubility (shown as a larger blood box) means gas rapidly moves into
blood, but concentration that reaches brain increases more slowly
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
control
Early apoptosis
• Developing rat
brain
• Exposure to a
combination
including
nitrous,
isoflurane &
midazolam
exposed
• Persistent
learning deficits
Late apoptosis