Adrenergic Pharmacology

Shi-Hong Zhang (张世红 ), PhDDept. of Pharmacology, School of Medicine, Zhejiang Universityshzhang713@zju.edu.cn

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