adrenergic pharmacology

Adrenergic Pharmacology

Sanhua Fang , PhDDept. of Pharmacology, School of Medicine, Zhejiang Universityfshfbzxhq@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 releaseTyrosine 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 Hypoglycemia2 Hypothermia3 Hypoxia4 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

sulin

inje

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 - Piloerection2 - Peripheral vasoconstriction3 - Thermogenesis

-Brown fat a) activationb) 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 Antagonists2 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

HPharmacological 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 patientsC. Metabolism• lipolysis , glycogenolysis , potentiating

insulin effects ~ hypoglycemiaD. 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

SummaryAgonist Receptor

specificityTherapeutic uses

epinephrine 1,21,2

• Acute asthma,• Anaphylactic(过敏性 ) shock,• in local anesthetics to

increase duration of action norepinephrine 1,2

1)• 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 •hypertensionSalbutemolTerbutalineRitodrine

•Asthma•Premature labor

SummaryAntagonist Receptor

specificityTherapeutic uses

PhentolaminePhenoxybenz-

amine (酚苄明 )

• pheochromocytoma• Peripheral vascular diseases• Local vasoconstrictor

extravasationprazosin • hypertensionpropranolol • Hypertension

• Glaucoma• Migraine• Hyperthyroidism• Angina pectoris• Myocardial infarction

timolol • Glaucoma • hypertension

AtenololMetoprolol

• hypertension

labetalol • hypertension

Drugs That Act in the Central Nervous System

Central Nervous System Diseases(Neuropsychological diseases ，神经精神疾

病 )• Causes ： -Trauma -Infections -Degeneration -Structural defects -Tumors -Autoimmune disorders -Ischemia -etc

• Diseases ： -Encephalitis （脑炎） -Alzheimer’s Disease （老年痴呆） -Parkinson’s Disease （帕金森病） -Multiple Sclerosis （多发性硬化） -Insomnia （失眠） -Epilepsy （癫痫） -Pain （疼痛） -Stroke （中风） -Schizophrenia （精神分裂症） -Depression （抑郁症） -Mania （躁狂症） - etc

excitationinhibition

Balance in the CNS function

Classification of CNS drugs

• Sedative-hypnotics • Antiepileptic and anticonvulsive drugs• Drugs for Parkinson’s disease• Analgesics and anesthetics• Central stimulants

Neurological:

Classification of CNS drugs

• Antipsychotic drugs• Antidepressant and antimanic drugs• Drugs for dementia

Psychological:

NOTE: Besides to treat neuropsychological diseases, CNS drugs are important tools for studying CNS physiology and pathogenesis of disease.

Sedative-Hypnotic Drugs

- is characterized by excessive, exaggerated anxiety and worry about everyday life events with no obvious reasons for worry;- can be extremely debilitating, having a serious impact on daily life.

Anxiety

Insomnia:

-1-5%, more in old women; - trouble in falling asleep or too easily to be waken up; - can be primary or secondary; - harmful to daily life: excessive daytime sleepiness and a lack of energy, feel anxious, depressed, or irritable.

Graded dose-dependent effect

Chemical classification• Benzodiaazepines: diazeepam ( 安定 ), nitraazepam ( 硝西泮 ),

oxaazepam ( 奥沙西泮 ), estazolam ( 艾司唑仑 ), triazolam ( 三唑仑 ), flunitrazepam ( 氟硝西泮 ) ， etc (with same nucleus and different substituents)

• Barbiiturates: pentobarbital( 戊巴比妥 ), phenobarbital ( 苯巴比妥 ), thiopental ( 硫喷妥 ), etc • Others: buspirone ( 丁螺环酮 ), chloral hydrate ( 水合氯醛 ),

meprobamate ( 甲丙氨酯 ), etc• Antipsychotic (e.g. chlorpromazine), antidepressant drugs

(e.g. amitriptyline) and certain antihistaminic agents (e.g. diphenhydramine)

1. 1. ADMEADME(1) Oral absorption(2) Lipid solubility-dependent distribution (across

BBB), placcental penetrabbility (effect on fetus)(3) Hepatic metabolism ---active metabolites

A.A. Benzodiazepines Benzodiazepines

Disassociation of effect and half-life time

1. 1. ADMEADME

Classification according to action duration Short-acting: triazolam, laorazepam, oxazepam, etc Medium and long-acting: diazepam, nitrazepam,

chlordiazepoxide, flurazepam etc

(4) Urinary excretion

A.A. Benzodiazepines Benzodiazepines

2. 2. Pharmacological effects and clinical usesPharmacological effects and clinical uses(1) Reduction of anxiety: at small doses, used as

anxiolytics (not work on schizophrenia)

(2) Sedative-hypnotic effects -- -- at relatively higher doses -- no anesthetic effect -- no enzyme induction -- increase stage 2 of NREM, no remarkable effect on REM,

decrease slow wave sleep

A.A. Benzodiazepines Benzodiazepines

NREM

Stages 3

Stages 3 and 4 are deep sleep.Growth hormone is released during these stages.

Slow wave sleep

BZs

2. 2. Pharmacological effects and clinical usesPharmacological effects and clinical uses(2)Sedative-hypnotic effects -- used for insomnia and preanesthetic medication (as adjuvant to anesthetics)

(3) Antiepileptic and anticonvulsant effects -- inhibit epileptiform activity

-- used for seizures, status epilepticus (i.v.),

convulsion

A.A. Benzodiazepines Benzodiazepines

(4) Centrally acting muscle relaxant effect -- relaxing the spasticity of skeletal muscle, probably

by increasing presynaptic inhibition in the spinal cord.

-- used for the treatment of skeletal muscle spasms caused by central or peripheral diseases.

A.A. Benzodiazepines Benzodiazepines

(5) Others --dose-dependent anterograde amneesic effects ( i.v.） - for unpleasant examination or therapy (cardioversion,

endoscope, etc)

--respiratory and CVS effects (central inhibition)

-- alleviate the withdraw syndromes

A.A. Benzodiazepines Benzodiazepines

3. Action 3. Action MechanismsMechanisms(1) Sites of action: mainly acts on limbic system

(anxielytic) and midbrain reticular formation (hypnotic).

A.A. Benzodiazepines Benzodiazepines

A.A. Benzodiazepines Benzodiazepines

(2) Interaction with GABAA receptor -- Increase the frequency of GABA-induced

chlorine channel-opening events -- GABA dependent effect

3. Action 3. Action MechanismsMechanisms

γ subunit

(2) Interaction with GABAA receptor

Hyperpolarization

4. Adverse effects(1) Central depression Most common: drowsiness and confusion ataxia; cognitive impairment (hangover effect)

Additive with other CNS depressant drugs

Antagonized by BZ receptor antagonist flumazenil(2) Tolerance: lethal dose is not altered (3) Dependence: compulsive misuse Withdrawal syndrome (shorter acting agents): restlessness,

anxiety, weakness, orthostatic hypotension and generalized seizures

A.A. Benzodiazepines Benzodiazepines

(3) Others Respiratory and CVS reactions Teratogenic effects (Pharmaceutical Pregnancy Category

D or X)

(4) ContraindicationsMyasthenia gravis (重症肌无力 )Infants < 6 monthsPregnant and lactation mothersElderly with heart/lung/liver/kidney dysfunctionWorkers requiring mental alertness and fine motor

coordination

A.A. Benzodiazepines Benzodiazepines

1. ADME - hepatic enzyme inducer - alkalizing urine (sodium bicarbonate): excretion 2. Pharmacological effects and clinical uses (1) Sedative-hypnotic effects - REM decrease (2) Antiepileptic and anticonvulsant effects (3) Preanesthetic medication

B.B. Barbiturates Barbiturates

• increase the duration of the GABA-gatedchloride ion channel openings• GABA-mimetic at high dose – GABA independent efficacy

Graded dose-dependent depressive effect of sedative- hypnotics on central nervous system function

Benzodiazepines

Barbiturates

3. Adverse effects

(1) Central depression: after (hangover) effect

(2) Tolerance and dependence: repetitive use, long-term use, REM rebound

(3) Porphyria (enhances porphyrin synthesis): anemia, photosensitive skin injury

B.B. Barbiturates Barbiturates

3. Adverse effects

(4) Acute poisoning ---supporting therapies: oxygen inhalation, unblocked

respiratory tract (tracheootomy), central stimulants ---alkalizing urine ---hemodialysis

B.B. Barbiturates Barbiturates

Marilyn Monroe (1926-1962)

• Chloral hydrate Sedative-hypnotic effects Anticonvulsant effect: children (anal administration)

• Buspirone: anxiolytic, minimal abuse liability

• zolpidem, zaleplon: hypnotics, selective BZ binding

C. Other sedative-hypnotic drugs

• Antipsychotics• Antidepressant drugs • Antihistaminic agents• Ethanol• Melatonin (pineal hormone)

C. Other sedative-hypnotic drugs

Summary of clinical uses of sedative-hypnotics

Antiepiletpic Drugs (AEDs)

-----Epilepsy is a chronic disorder characterized by recurrent seizures, which are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons

International Classification of Epileptic Seizures:

Partial Onset Seizures

– Simple Partial

– Complex Partial (consciousness is affected)

– Partial Seizures with secondary generalization

Source of seizure

International Classification of Epileptic Seizures: Primary Generalized Seizures

–Absence (Petit Mal)–Generalized

Tonic+Clonic (Grand Mal)

–Tonic–Atonic–Clonic and myoclonic

Stereotypical complex partial seizures

Tonic phase

Clonic phase

CyanosisCry

Salivary frothingJerking of the limbs

Post-ictal phase

Patient feels lethaargic and confused after seizuresOften sleeps

Loss of consciousness, Fall, crying, and generalized tonic stiffeningoften with bladder incontinence

Simultaneous bilateral cortical seizure attack

Epilepsy treatment

• Epilepsy affects 1% population worldwide• Drug treatment is the main approach.• ~20-30% of patients develop refractory

epilepsy.• New drugs and new approaches are

needed.

AEDs Effective as Monotherapy (Single Agent)

Partial (Localization

Related)

• Phenytoin• Carbamazepine• Valproate• Oxcarbazepine• Lamotrigine• Topiramate• Gabapentin

Generalized

• Phenytoin• Carbamazepine • Valproate

– (GTC and absence)• Ethosuximide - (absence)• Topiramate

– (GTC)• Lamotrigine

– (absence)

Bold= new generation AED

New AEDs effective as adjunctive treatment for refractory epilepsy

Partial

• Topiramate• Levetiracetam• Pregabalin • Zonisamide • Oxcarbazepine

• Lamotrigine• Gabapentin• Tiagabine

Generalized

• Topiramate• Levetiracetam• Lamotrigine

– Data from randomized placebo controlled trials

Drugs in red are generally considered high potency

Effects of three antiseizure drugs on sustained high-frequency firing of action potentials by

cultured neurons.

Mechanisms of AEDs

• Modification of ionic conductance. - Na+ - K+

- Ca2+ • Enhancement of GABAergic (inhibitory)

transmission• Diminution of excitatory transmission

Drugs which act on Na+ channel

• Phenytoin• Carbamazepine• Oxcarbazepine• Lamotrigine

Phenytoin苯妥英钠• Effective against partial

seizures and generalized tonic-clonic seizures

• Non-linear kinetics• Therapeutic range = 10-20

ug/ml–Levels above 20 cause ataxia and nystagmus ( 眼球震颤 )

• Half life = 12-24 hours, slow effect

• Hepatic metabolism–CYP3A enzyme pathway

Oral Dose: about 5 mg / kgwww.boomer.org/c/p4/c21/c2103.html

Phenytoin -----Mechanisms of action

• Binding to and hence prolonging the status of inactivated state of Na+ channels (main mechanism)

• Blocking L- and N- type Ca2+ channels (inhibits release of transmitters, stabilizes membrane)

• Chronic neuropathic pain: trigeminal neuralgia ( 三叉神经痛 ), sciatica ( 坐骨神经痛 ), glossopharyngeal neuralgia ( 舌咽神经痛 )

• Arrhythmia--b anti-arrhythmia drug

Phenytoin ---Other uses

Phenytoin side effects• CNS: nystagmus, diplopia, ataxia, depression• Local irritating (alkaline): gingival hyperplasia, GI upset,

phlebitis• Hematologic complications - Megaloblastic anemia: folic acid loss - Agranulocytosis• Idiosyncratic or allergic reactions

- Rash, up to 10%, can be very serious - stop drug- Fever- Hepatitis

• Skeleton: osteomalacia ( 骨软化 , Vit D degradation↑)• Others: birth defects (fetal malformations, class D), hirsutism

hirsutismGingival hyperplasia

Phenytoin side effects

Mephenytoin: more severe adverse effects

Ethotoin: Less effective

Carbamazepine卡马西平• Mechanisms: blockade of

Na+ and Ca2+ channels, potentiation of GABA transmission

• Half life = 8-12 hours (steady state)

• Like phenytoin, metabolized by CYP3A pathway (inducer itself)

• Effective against partial and generalized tonic-clonic seizures, trigeminal neuralgia and mania

• Safety and Toxicity–peak effect- diplopia, ataxia–rash 5-10%–rare marrow suppression aplastic anemia and agranulocytosis–rare hepatitis–frequent hyponatremia at high dose–fetal malformations (class D)

• Dose in Adults– 200 mg once a day – After several days, 200 mg

twice a day– Slowly titrate to 10 mg/kg

• Therapeutic = 6 -12 ug/ml

Watch for Rash!

Carbamazepine

Oxcarbazepine --- less effective --- improved toxicity profile (fewer hypersensitivity reactions less hepatic enzyme induction)

Lamotrigine拉莫三嗪• Na+ channel blocker• Ca2+ channel blocker• Moderate effective against both

partial and generalized epilepsy (absence/myoclonic) as add-on or monotherapy

• Hepatic metabolism, significant drug interactions with valproate (CYP inhibitor) leads to twofold increase in half-life time (level and side-effects increase)

• Linear clearance• Half life -24 hours• Start 25 mg/day, titrate slowly to 300-

500 mg/day

• 10% risk of rash• Dizziness,

headache, diplopia, nausea, somnolence

• Class C in pregnancy, significantly lower than other

Drugs acting at the chloride channel

• Benzodiazepines–Binds to BZD specific receptors

• Phenobarbital –Binds to barbiturate specific receptors

• Gabapentin– GABA analogue, alters GABA metabolism, release

and reuptake, effective as an adjunct against partial seizures and generalized tonic-clonic seizures

• Valproate –Decreases GABA degradation in presynaptic terminal

Valproate丙戊酸 • Broad spectrum: - absence: ethosuximide

first choice - generalized tonic-clonic - partial• Blocks Na+ channels and

NMDA receptors• Increases GABA levels

– Facilitates GAD– Inhibits GAT-1– Inhibits degradation of

GABA• dose = 15-20 mg/kg to start

using a TID schedule

• GI side effects (abdominal pain and heartburn)

• Obesity + Metabolic syndrome (weight gain, increased appetite, and hair loss)

• Hepatotoxicity, elevates ammonia (liver function monitoring required)

• Fine tremor• Serious neural tube (spina

bifida, split spine) and cardiac defects in fetus in 1% (Pregnancy Category D)

During and After Valproate Therapy

It should be noted that valproate is an effective and popular antiseizure drug and that only a very small number of patients have had severe toxic effects from its use.

Drugs which primarily affect potassium channel

• Levetiracetam– Blocks voltage gated K+

channels in hippocampus neurons

– Blocks kainate receptors – Affects GABA receptors– Blocks action potentials,

and paroxysmal depolarizing shifts

Madeja et al Neuropharamacology 2003

Drugs which primarily affect potassium channel

Levetiracetam• Effective for partial

epilepsy with or without generalization

• High Potency-----75% reduction in

seizures in over 20% of refractory patients

• Few side effects except: – Somnolence, asthenia,

and dizziness– Pregnancy category C

Drugs which affect Kainate and AMPA receptors

• Topiramate• Zonisamide

Topiramate托吡酯• Mechanisms -Multiple

– Blocks AMPA+kainate receptors

– Blocks Na+ and Ca2+ channels

– Potentiates GABA transmission

• Effective against both partial and generalized epilepsy

• Excreted primarily in urine• Start at 25 mg/day, titrate

to 300-500/day

• Behavioral /Cognitive problems common (somnolence, fatigue, dizziness, cognitive slowing, paresthesias, nervousness, and confusion)

• Low risk of rash• Causes weight loss• Class D in pregnancy (oral

clefts)• High Potency

----75% reductions in over 20% of refractory patients

Drugs which affect calcium channels

Ethosuximide 乙琥胺• Mechanism

– Blocks T-Ca2+ channels in thalamic neurons (T-type calcium currents are thought to provide a pacemaker current in thalaamic neurons responsible for generating the rhythmic cortical discharge of an absence attack)

• Effective against absence seizures• Long half life time 40~50h• Effective dose range 750–1500 mg/d• Adverse effects: gastric distress (stomachache, nausea,

vomiting), CNS response (fatigue, dizziness, headache, euphoria, sleepiness, hiccup)

Teratogenicity 致畸作用• All AEDs cause fetal

malformations in at least 6% of infants, such as neural tube defects, mouth malformation, cardiopathy.

• Highest risk with phenytoin, valproate, phenobarbital, and carbamazepine, etc (Class D drugs)

• Folate supplementation prevents neural tube defects (split spine, 脊柱裂 ).

When to initiate treatment?

Case Study: Initiation of Treatment

• A 22 year old female sustains a head injury with loss of consciousness

• Two years later she develops a single secondarily generalized tonic-clonic seizure

• MRI and EEG are normal

• You should

1. Instruct her not to drive. Report the event to the department of public health or DMV

2. Wait until a second seizure, and then initiate an AED

3. Initiate a pregnancy class C AED now.

4. Initiate, phenytoin, valproic acid, phenobarbital, or carbamazepine now

Initiation of Treatment

• Consider all the facts. – After a first seizure, the risk of subsequent

epilepsy is 35% within 1-2 years– After a second seizure, the risk is over 90%

• It depends on the level of risk and the patient’s situation

Initiation of Treatment

Increased risk• Known symptomatic cause• Partial seizures• Family history of epilepsy• Abnormal electroencephalogram (particularly generalized spike-and-slow wave)• Abnormal findings on neurologic examination• Abnormal imaging findings

Decreased risk• Idiopathic cause• Generalized seizure• No family history of epilepsy• Normal electroencephalogram• Normal findings on neurologic examination

Initiation of Treatment

• the risk-benefit ratio of the anticonvulsant treatment must be carefully assessed in patients after a single seizure

• Avoid valproic acid in a woman of childbearing potential. Answer 4 is clearly a poor choice.

Initiation of Treatment

Initiation of Treatment