Adrenergic Pharmacology
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Transcript of Adrenergic Pharmacology
Adrenergic Pharmacology
Sanhua Fang , 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 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