Adrenergic Pharmacology
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Transcript of Adrenergic Pharmacology
Adrenergic Pharmacology
Shi-Hong Zhang (张世红 ), PhDDept. of Pharmacology, School of Medicine, Zhejiang [email protected]
Noradrenergic Nerve: Synthesis, storage and release of NETyrosine
tyrosine hydroxylase (TH)
L-DOPA
DOPA decarboxylase
dopamine (DA)
dopamine beta-hydroxylase (DBH)
norepinephrine (NE)
• Uptakeneurotransmitter 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
Chromaffin cell
NEPNMT
NE EPI 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 turnoverbut generated mostly from periphery
VMA(香草扁桃酸 ): sometimes used as an index of NE turnover
Sulfate conjugates also prevalent
or MHPG
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
Adrenergic Receptor Subtypes & G-Protein Coupled Mechanisms
q
去氧肾上腺素
异丙肾上腺素
可乐定
Four Major Activators of the Adrenergic System
1 Hypoglycemia
2 Hypothermia
3 Hypoxia
4 Hypotension
• Hypoxia - response is mainly cardiovascular: 1 receptors via
SNS NE increase heart rate & contractility, resulting in
greater cardiac output; 2 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 2
vasodilation in muscle increases glucose (as well as oxygen)
delivery.
Response toHypoglycemia(insulin injection)
The release of E (and to a lesser
extent NE) by the adrenal is in direct response to falling
blood glucose levelsIn
suli
n i
nje
ctio
n
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 2 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 (2) & inhibiting release of insulin (2)
Lypolysis• Lipases are stimulated by (esp. 3) receptors
Energy Mobilization by Epinephrine
Response to Hypothermia:
1 - Piloerection
2 - Peripheral vasoconstriction
3 - Thermogenesis
-Brown fat
a) activation
b) proliferation
receptors1 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
receptors
1 receptors: contractility↑, automaticity↑, conduction↑,
oxygen-consumption↑, cardiac output↑: heart stimulation; increased lipolysis
2 receptors: relaxation of bronchial smooth muscles:
bronchodilation; slight vasodilation; increased muscle and liver glycogenolysis; increased release of glucagon
3 receptors: lipolysis, thermogenesis
Summary: Adrenoceptors
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
苯乙胺
麻黄碱
• Receptor activation•Strong efficacy•Short duration•No entry to CNS
•Resistant to MAO
Methamphetamine 甲基苯丙胺
• Non-catecholamine
– Indirect-acting by causing the release of stored catecholamine.
– Not inactivated by COMT; some are poor substrate for MAO
(orally active, a prolonged duration of action)
– Greater access to the CNS
• Catecholamine
– High potency in activating or receptors
– Rapid inactivation by COMT and by MAO
– Poor penetration into the CNS
苯乙胺
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 effect1, 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)
(3) Cardiac effects : weak direct stimulation (1);
inhibition via reflex (in vivo)
Net result: little cardiac stimulates
Norepinephrine
Effects of Norepinephrine on BP and HR
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
Norepinephrine
• 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 )
Phenylephrine (去氧肾上腺素 )Methoxamine (甲氧明 )
1 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
• ClonidineAdverse 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.
2 receptor agonists
Pharmacological effects : 1, 2, 1, 2
receptor agonists
(1) Cardiac effects
1: contractility (positive inotropic),
HR (positive chronotropic),
cardiac output , oxygen consumption , induces arrhythmia
Epinephrine, Adrenaline
Pharmacological effects : 1, 2, 1, 2
receptor agonists(2) Vascular effects 1 : vasoconstriction (skin, mucous, viscera),
especially at larger doses
2 : vasodilatation of skeletal muscles
and coronary vessels
Epinephrine, Adrenaline
Concentration-dependent response in vascular smooth muscle to epinephrine
Predominant Effectslow [EPI] β2 > αhigh [EPI] α > β2
(3) Blood pressure- two phases
Systolic BP, Diastolic BP↓(slight) , pulse pressure
Epinephrine
(4) Respiratory
2 : 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 (2)
(6) Eye: intraocular pressure ↓ (α2)
(7) Metabolic effects
blood glucose (2 and 1,2, hyperglycemia);
free fatty acids (, lipolysis)
Epinephrine
Clinical uses
Systematic uses:
• Cardiac arrest
• Anaphylactic shock (过敏性休克 )
• Acute bronchial asthma
Topical uses:
• Adjuvant of local anesthesia
• Bleeding
• Glaucoma
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)
Epinephrine
Properties : - Promoting release of NE, weak agonist effects on 1 、 2 、
1 、 2 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 麻黄碱
EpinephrineEphedrine Methamphetamine
CH3
NHCHCH2
CH3CH3
NHCH
OH
CH
CH3
HO
HO CH
OH
CH NH
CH3
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
Ephedrine
Pharmacological effects:
, receptor, dopaminergic
receptor agonists(1) Cardiac effects: 1 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)
Dopamine
Pharmacological effects: 1 , 2 receptor agonists, NE releaser
(1) Cardiac effects (1 receptor)
(2) Vascular effects and blood pressure
2 receptor: dilatation of skeletal
muscles and coronary vessels ; SP , DP or , pulse pressure
(3) Bronchodilatation (2 receptor)
(4) Metabolism
Promoting effects as epinephrine
Isoproteerenol, Isopreenaline:
Effects of catecholamines ( therapeutic doses )
Predominant Effects:NE : & 1 effectsEPI : 1, 2 then at higher concentrations effects predominateISO: 1 and 2
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
Isoproterenol
Dobutamine (多巴酚丁胺)
1 receptor agonists
• Heart failure (after cardiac surgery or congestive HF or acute myocardial infarction; short-term treatment)
• Cardiac stimulation
Terbutaline (特布他林 )• Uses: Bronchial asthma dilation of bronchial smooth muscle; 2 > 1 agonist
(partially selective): preferential activation of pulmonary
2 receptors by inhalation.
Use: Premature Labor (ritodrine).
• Adverse effects:
headache, cardiac stimulation and skeletal muscle fine
tremor (2 receptors on presynaptic motor terminals; their
activation enhances ACh release).
2 receptor agonists
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
N
NCH3
HO
N CH2
H
Pharmacological effects(1) Vasodilatation
Blocking 1 receptor: vasodilation in both arteriolar
resistance vessels and veins
(2) Cardiac stimulation
Reflex; blocking 2 receptor ~ NE release (3) Cholinergic and histamine-like effects
Contraction of GI smooth muscles,
Gastric acid secretion
Competitive, nonselective
Clinical uses
(1) Decrease blood pressure• Hypertension from pheochromocytoma (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
Phentolamine
Pheochromocytoma is a rare catecholamine-secreting tumor derived from chromaffin cells of the adrenal medulla that produces excess epinephrine.
• Hypertension & Crises• Elevated Metabolic Rate
-heat intolerance-excessive sweating-weight loss
• Temporarily manage with -adrenergic antagonists (1 & ±)
Pheochromocytoma
• Irreversible, nonselective ( 1 and 2 antagonists )
• Long-acting
• Similar to phentolamine in actions and clinical uses
Phenoxybenzamine 酚苄明
1 receptor antagonists
• Prazosin: treatment for hypertension
• 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
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.
receptor antagonists
Pharmacological effects(1) receptor blockadeA. Cardiovascular effects :• Depressing heart: reduction in HR, A-V
conduction, automaticity, cardiac output, oxygen consumption
• Hypotension: peripheral blood flow , hypotensive effects in hypertensive
patients
receptor antagonists
(1) receptor blockadeB. Bronchial smooth muscles• induces bronchial smooth muscle contraction
in asthmatic patients
C. Metabolism• lipolysis , glycogenolysis , potentiating
insulin effects ~ hypoglycemia
D. Renin secretion• decreasing secretion of renin
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
receptor antagonists
Circulation of Aqueous humorCirculation of Aqueous humor
Clinical uses(1) Arrhythmia: supraventricular, sympathetic
activity (2) Hypertension
(3) Angina pectoris and myocardial infarction
(4) Chronic heart failure
(5) Others: hyperthyroidism, migraine headache, glaucoma (timolol)...
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.
receptor antagonists
• 1, 2 receptor blocking
• no intrinsic activity• first-elimination after oral administration,
individual variation of bioavailability
Propranolol
Timolol• For the treatment of glaucoma (wide-angle)
1receptor antagonists, no intrinsic activity
•
• atenolol : longer t1/2, once daily
• usually used for the treatment of hypertension
Atenolol, Metoprolol
α, receptor antagonists
• α, β receptor blocking, β> α
• usually used for treatment of hypertension
Labetalol
Summary
Agonist Receptorspecificity
Therapeutic uses
epinephrine 1,21,2
• Acute asthma,• Anaphylactic(过敏性 ) shock,• in local anesthetics to
increase duration of action
norepinephrine 1,21)
• shock
isoproterenol 1,2 • Asthma• As cardiac stimulant
dopamine Dopaminergic,
• Shock,• Congestive heart failure
dobutamine • Heart failure
SummaryAgonist Receptor
specificityTherapeutic uses
Ephedrine(麻黄碱 )
•asthma•as a nasal decongestant
Metaraminol (间羟胺 )
•Shock•hypotension
Phenylephrine (苯肾上腺素 )
•supraventricular tachycardia •glaucoma•as a nasal decongestant
Methoxamine (甲氧胺 )
•supraventricular tachycardia
Clonidine •hypertension
SalbutemolTerbutalineRitodrine
•Asthma•Premature labor
SummaryAntagonist Receptor
specificityTherapeutic uses
PhentolaminePhenoxybenz-
amine (酚苄明 )
• pheochromocytoma• Peripheral vascular diseases• Local vasoconstrictor
extravasation
prazosin • hypertension
propranolol • Hypertension• Glaucoma• Migraine• Hyperthyroidism• Angina pectoris• Myocardial infarction
timolol • Glaucoma • hypertension
AtenololMetoprolol
• hypertension
labetalol • hypertension
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
• 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 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
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