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Title: pharmacology


1
pharmacology
  • General introduction
  • Drugs acting on efferent nervous system
  • Drugs acting on central nervous system
  • Drugs acting on cardiovascular system
  • Drugs acting on viscera
  • Chemotherapeutic agents

2
Chapter 5 Intrduction to Pharmacologyof
Efferent Nervous System
  • Zhang Bin
  • Institute of Pharmacology
  • School of Medicine
  • Shandong University

3
Organization of Nervous system
4
efferent nervous system (ENS)
  • autonomic nervous system (vegetative nervous
    system)
  • somatic motor nervous system

5
Efferent neurons of the autonomic nervous system
6
Classification of ENS according to the released
neurotransmitters
  • cholinergic nerve acetylcholine (Ach)
  • noradrenergic nerve noradrenaline ( NA)

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Classification of ENS
Central nervous system
Ach skeletal muscle
somatic motor nerve
Ach NA Ach
Ach sweat glands
heart, vessel, smooth muscle
sympathetic nerve
Ach adrenal medulla
Parasympathetic nerve
Ach Ach
glands, smooth muscle, heart
9
Section 1 Neurotransmitter and
Receptor of ENS
  • Neurotransmitter of ENS
  • The receptors of ENS

10
?. Neurotransmitter of ENS
  • 1.Development of neurotransmitter theory
  • 100 years ago Chemical transmission
  • electronic
    transmission
  • 1946 Von Euler NA (noradrenaline)
  • 1921 loewi double frog heart experiment
  • 1926 Dale Ach (acetylcholine)

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2.Biosynthesis, storage, release and termination
of neurotransmitters
  • Ach (acetylcholine)
  • NA (noradrenaline)

13
inhibitor
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2.Biosynthesis, storage, release and termination
of neurotransmitters
  • (1)Biosynthesis
  • choline acetyl coenzymeA
    Ach
  • tyrosine dopa DA
    NA

16
(2) Storage
  • ATPprotein store in vesicles

Ach NA
17
(3)release
  • exocytosis
  • quantal realease
  • cotransmission

18
(4)Termination
  • Ach acetylcholinesterase (AchE)
  • in synapse
  • NA uptake1 (neuronal uptake ) 75-90
  • storage in vesicles\ MAO
  • uptake2(non-neuronal uptake)
  • COMT\MAO

19
?. The receptors of ENS
  • Classification, Distribution and Effect

20
Choline receptors (Cholinoceptors )
  • M-R muscarine
  • N-R nicotine

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Cholinoceptors
  • M-R
  • M1-R ganglion, CNS
  • M2-R heart, presynaptic sites (negative
    feedback), CNS
  • M3-R exocrine glands, smooth muscle,
    endothelium, CNS
  • M4 R exocrine glands, smooth muscle, CNS
  • M5 -R CNS

23
Cholinoceptors
  • N-R nicotine
  • NM-R skeletal muscle
  • NN-R ganglion and CNS

24
adrenoceptor NA AD
  • a-R
  • a1-R
  • postsynaptic effector cells
  • (especially smooth muscle)
  • a2-R
  • presynaptic nerve terminals (negative
    feedback),
  • platelet, smooth muscle, lipocytes

25
adrenoceptor
  • ß-R
  • ß1-R postsynaptic effector cells,
  • (especially heart, lipocytes,)
  • presynaptic nerve terminals
  • ß2-R postsynaptic effector cells,
  • (especially smooth muscle)
  • ß3-R postsynaptic effector cells,
  • (especially lipocytes)

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Classification of receptor according to their
structure
  • G-protein-coupled receptor
  • ?-R, ?-R, M-R, DA-R, 5-HT-R
  • Ligand-gated receptors
  • N-R

28
Structure of G-protein-coupled Receptor
29
Molecular Mechanism of Gq-protein-coupled Receptor
30
Molecular Mechanism of Gi/s-protein-coupled
Receptor
31
Structure of ligand-gated ion channel Receptor
32
Molecular Mechanism of ligand-gated ion channel
receptor
33
  • 1. Cholinoceptors
  • M-R G-protein-coupled receptor
  • M1-RGq-protein-coupled receptor
  • M2-R-Gi-protein-coupled receptor
  • N-R ligand-gated ion channel receptor
  • 2. adrenoceptor G-protein-coupled receptor
  • a1 R Gq-protein-coupled receptor
  • a2 R Gi-protein-coupled receptor
  • ß-R Gs-protein-coupled receptor

34
Molecular Mechanism of Receptor
G-protein-coupled receptor
(-) PKA
N-R
Na , K, Ca2
ligand-gated receptor
35
terminology
  • adrenergic
  • adrenergic receptor
  • cholinergic
  • cholinergic receptor
  • postsynaptic receptor
  • presynaptic receptor

36
Section 2The physiological actions of ENS
  • Co-innervation and Dominant Theory
  • Sympathetic actions
  • fight and flight response
  • Parasympathetic actions
  • rest and digest response

37
Section 3 The basic mechanisms of actions of ENS
drugs
  • 1.Direct action of receptors
  • agonist
  • blocker (antagonist)
  • 2.lnfluence of neurotransmitters
  • biosynthesis
  • release
  • storage
  • conversion

38
Section 4 The classification of the ENS drugs
39
(?)??????
40
Chapter 6 parasympathomimetics
  • Cholinoceptor agonists (cholinomimetics)
  • Anticholinesterase agents (cholinesterase-inhibiti
    ng drugs)
  • Drugs of enhancers of ACh release

41
Cholinoceptor Agonists
  • M-R agonists
  • Choline esters acetylcholine (ACh)?
  • alkaloids pilocarpine?
  • N-R agonists
  • nicotine

42
Section 1 M-R agonists
  • Acetylcholine (ACh)
  • 1. unstable
  • 2. low selectivity
  • 3. administration route

43
  • Pharmacological actions
  • Directly activate M-R, N-R
  • muscarinic actions small dose
  • nicotinic actions large dose

44
1.muscarinic actions small dose
  • 1.cardiovascular system
  • vessel dilate
  • a. NO release?
  • (M3 R ?EDRF(NO) ??GC ?cGMP?? intracellular Ca2?)
  • b. NA release?
  • BP (HR)
  • Heart depress
  • negative (chronotropic, dromotropic,
    inotropic) effect

45
1.muscarinic actions small dose
  • 2.glands ?
  • 3.gastrointestinal tract
  • motility increase, secretion stimulation
  • 4. urinary bladder
  • detrusor muscle (???)contraction,
  • trigone and sphincter relaxation
  • 5.eye
  • sphincter muscle of iris (??) contract miosis
  • ciliary muscle contract near vision

46
  • 2.nicotinic actionslarge dose
  • NN-R dominant nerve actions
  • NM -Rskeletal muscle contraction

47
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49
alkaloids
  • Pilocarpine(?????,????)
  • Muscarine(???)
  • Arecoline (???)
  • Oxotremorine(?????)

50
Pilocarpine
  • Pharmacological actions selectively activate M-R
  • 1.Eye
  • miosis pupiliary sphincter
  • decrease intraocular pressure
  • spasm of accommadation ciliary muscle

51
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  • 2. Glands secrete increasingly
  • (sweat gland, salivary gland)
  • 3. Smooth muscle
  • 4. Cardiovascular system

54
Clinical uses
  • 1.Glaucoma(???)
  • angle-closure glaucoma
  • open-angle glaucoma

55
What is Glaucoma?
  • increased pressure within the eye. Cells inside
    the eye produce aqueous humor that maintains the
    shape of the eye and nourishes the tissues inside
    the eye. The balance of fluid production and
    drainage is responsible for maintaining normal
    pressure within the eye.
  • In glaucoma, the drain becomes clogged but the
    eye keeps producing fluid. Therefore, the
    pressure in the eye increases. The increased
    pressure in the eye actually can cause the eye to
    stretch and enlarge

56
How does Glaucoma affect the eye?
  • Vision Loss. Pressure damage to the optic nerve
    and decreased blood flow to the retina, results
    in loss of vision. However, if the pressure in
    the eye remains uncontrolled, the retina
    degenerates and vision is permanently lost.
    Permanent blindness can occur within several
    hours if the pressure is very high and the
    glaucoma develops rapidly
  • Pain. Humans have normal intraocular pressures
    between 10 and 20 mmHg. Glaucoma often results in
    pressures of 20-28 mmHg in humans. The pain
    persists in the form of a constant headache or
    migraine. This discomfort can result in decreased
    activity, less desire to play, irritability, or
    decreased appetite

57
  • 2.iritis(???),
  • iridocyclitis(??????)
  • 3.others dry mouth

58
Adverse reactions
59
Muscarine(???)
  • Amanita muscaria
  • (???)

Inocybe(?????)
Clitocybe(????)
60
Section 2 N-R agonists nicotine
  • Nicotine

from tobacco Action NM, NN, CNS and
dependence (double phase) Tobacco
poison Hypertension, coronary heart disease,
cerebrovascular disease, cancer , Atherosclerosis
61
China
  • Largest tobacco productive country,
  • Largest tobacco consumption country
  • No smoking!
  • Stop smoking!

62
Section 3 Anticholinesterase Agents
  • Cholinesterase
  • true Cholinesterase (AChE)
  • Pseudocholinesterase

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Anticholinesterase Agents-----indirect acting
cholinomimetics
65
Classification according to structure
  • non-covalent bonding agents
  • Edrophonium chloride (????) strong polarity,
    short
  • tacrine (???) strong lipophilia, long
  • donepezil (????) strong lipophilia, long
  • Carboxamide(????)
  • Physostigmine(????)
  • Pyridostigmine(????)
  • Demecarium(????)
  • rivastigmine(?????)
  • orgnaophosphorus compound(??????)

66
??? ??? BBB ????
???? ?? ? ?
??? ?? ? ?
???? ?? ? ?
67
Classification according to pharmacological
property
  • Reversible Anticholinesterase agents
  • irreversible Anticholinesterase agents

68
  • Mechanisms of actions
  • Pharmacological actions
  • 1. eye
  • 2. gastrointestinal tract(esophagus,
    stomach, intestine)
  • 3. motor end plate
  • 4. glands
  • 5. cardiovascular system

69
Clinical Uses
  • 1. Myasthenia gravis
  • (?????)
  • Neostigmine
  • Pyridostigmine(????)
  • Ambenonium chloride
  • (????)

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Clinical Uses
  • 2. Postoperative abdominal distension Urinary
    retention Neostigmine
  • 3. glaucoma Physostigmine(????)
  • Demecarium(????)

72
  • 4. intoxication of d-tubocurarine
    Neostigmine,Edrophonium chloride (????)
  • 5. Alzheimers disease
  • tacrine, donepezil, rivastigmine, galanthamin
  • 6. Supraventricular tachyarrhythmias

73
Common used agents
  • Reversible Anticholinesterase agents

74
Neostigmine(????)
  • actions
  • 1. Inhibit AChE
  • 2. Activate NM-R on motor endplate
  • 3. Strong effect on skeletal muscle
  • 4. Not into CNS

75
  • Uses
  • 1. Myasthenia gravis Skeletal muscle contraction
  • po, sc, im iv
  • 2. Postoperative abdominal distension Urinary
    retention
  • 3. intoxication of d-tubocurarine and atropine
  • 4. Supraventricular tachyarrhythmias
  • 5. Glaucoma

76
  • Adverse reactions
  • Cholinergic overexcitation
  • (cholinergic crisis)
  • Treatment
  • atropine
  • d-tubocurarine

77
Pyridostigmine (????)
  • Weaker than Neostigmine
  • slower than Neostigmine
  • Longer than Neostigmine
  • Not into CNS
  • Used to treat Myasthenia gravis
  • Contraindication
  • mechanical ileus,urinary obstruction

78
Physostigmine
  • characteristics
  • 1. Stronger than neostigmine
  • 2. Can enter CNS
  • 3. Have no direct action on R

79
  • actions
  • 1. eye
  • 2. systemic action
  • Uses
  • 1. Glaucoma
  • 2. Intoxication of anticholine agents
  • Atropine
  • Tricyclic antidepressant
  • Dibenzothiazine antipsychotics

80
  • Comparison to pilocarpine
  • 1. More rapid
  • 2. Stronger
  • 3. longer

81
  • Donepezil
  • Rivastigmine
  • Tacrine
  • Alzheimers disease

82
Reversible anticholinesterase agents
  • neostigmine\Pyridostigmine\Ambenonium\Galanthamine
    Myasthenia gravis
  • Physostigmine\Demecarium Glaucoma
  • Edrophonium chloride diagnostic test for

  • myasthenia gravis
  • Donepezil\rivastigmine\Tacrine\Alzheimers
    disease

83
Irreversible Anticholinesterase
Agents--Organophosphates
  • Mechanisms of intoxication
  • Pathway of intoxication
  • signs of acute intoxication
  • 1.M manifestation (muscarinic excess )
  • 2.N manifestation(nicotinic effects)
  • 3.CNS effects
  • Chronic intoxication

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Prevention and treatment of organophosphates
intoxication
  • Prevention
  • Treatment of acute intoxication
  • 1.maintenance of vital signs
  • 2.Decontamination to prevent further
    absorption
  • 3.Symptomatic treatment
  • 1) atropine 2) cholinesterase
    reactivator

86
Cholinesterase Reactivators
  • Pralidoxime iodide(PAM)????
  • Mechanisms of action
  • therapeutic effect
  • 1. inhibit Nm manifestationstrong
  • 2. inhibit M manifestationweak
  • 3. CNS

???????
????
???
???AChE
AChE
87
  • Pralidoxime chloride (PAM-Cl) ????
  • better water-solubility
  • im and iv
  • little adverse reaction

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Chapter 7 cholinoceptor-blocking drugs
  • M-R blockers
  • N-R blockers NN-R blockers
  • NM-R blockers

90
Muscarinic cholinoceptor -blocking drugs
  • Atropine and atropine-like alkaloids
  • Synthetic atropine substitutes

91
atropine-like alkaloids and their resources
  • ?? ?????
  • ??(atropa belladonna) ???(hyoscyamine )
  • ???(datura stramonium) ???
  • ???(datrua sp) ???? (scopolamine)
  • ??(hyoscyamus niger) ???
  • ?????(scopolia tangutica) ???? (anisodamine)

  • ???(anisodine

92
??
??
93
???
???
94
Atropine
  • pharmacological actions
  • block M-R
  • block NN-R in large dose

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pharmacological actions
  • 1. glands secretion?
  • salivary, sweatgt lacrimal, respiratory gtgastric
    acid
  • , pancreatic, intestinal juice
  • 2. eyes
  • (1) mydriasis
  • (2) increase intraocular pressure
  • (3) paralysis of accommodation

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  • 3. splanchnic smooth muscle relaxation
    (spasmodic)
  • GI tract, detrusor muscle of bladder
    significant
  • Bile tract, bronchial, uterine (??) weak

99
  • 4. heart
  • (1)HR
  • Therapeutic dose decrease (presynaptic
    M1blockade)
  • Large dose increase (block vagal effect on M2
    R)
  • (2) A-V conduction

100
  • 5.vessels dilation( in large dose)
  • (1) Direct effect
  • (2)Compensative reaction by temperature rise
  • 6.CNS excitation

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Organ sensitivity Gland gteye gtsplanchnic
smooth muscle gtcardiovascular system gtCNS.
103
Clinical Uses
  • 1. Anti-smooth muscle spasm
  • 2.  Pre-anaesthesia medication agent
  • 3.  Ophthalmological use
  • (1) iridocyclitis
  • (2) optometry
  • (3) examination of retina
  • 4. Bradyarrhythmias
  • 5. Shock (septic shock )Cautions
  • 6. Intoxication of organophosphate

104
adverse reactions
1.Common Side Effects
105
  • 2. Acute Poisoning
  • minimal lethal dose adults 80130mg

  • children-- 10mg
  • Prevention
  • 1. Decontamination to prevent further absorption
  • 2. Antidotes Parasympathomimetics
  • 3. Maintenance of vital signs

106
contraindictions
  • Glaucoma
  • prostatic hypertrophy

107
anisodamine(654-2)????
  • Characteristic of actions
  • 1.high selectivity(smooth muscle and vessels)
  • 2.little side effect (not pass through BBB)
  • Uses
  • 1.septic shock
  • 2.visceral colics.

108
Scopolamine(????)
  • Characteristics
  • 1.CNS actions depression (strong)
  • 2.peripheral actions glands strong
  • others
    weak
  • Uses
  • 1.preanaesthesia medication
  • 2. prevention motion sickness
  • 3. Parkinson disease
  • 4. traditional medicine anaesthesia

109
????
  • ??(??141203?)
  • ???
  • ???(??? )
  • ??????????????(??)
  • ????

110
Section 2 Synthetic atropine substitutes
  • Synthetic Mydriatics
  • Synthetic Antispasmatics
  • Selective M1 Antagonists

111
Synthetic Mydriatics
  • Homatropine(????)
  • Tropicamide(????)
  • Cyclopentolate(????)
  • Eucatropine(????)

112
Comparison of some mydriatics
drugs concentration() mydriasis mydriasis paralysis of accommodation paralysis of accommodation
drugs concentration() peak(m) duration(d) peak(h) duration(d)
atropine 1.0 3040 710 13 712
homatropine 1.02.0 4060 12 0.51 13
tropicamide 0.51.0 2040 0.25 0.5 lt0.25
cyclopentolate 0.5 3050 1 1 0.251
eucatropine 2.05.0 30 1/121/4
113
  • Uses
  • iridocyclitis
  • optometry
  • examination of retina

114
Synthetic Antispasmatics
  • Quaternary amines(???)
  • Propantheline bromide(?????,????)
  • 1. selective blockade of GI tract
  • 2. ulceration, GI spasm, bladder stimulation
  • 3. neuromuscular block action toxic dose
  • 4. low BBB permeability

115
  • Quaternary amines(???)
  • Ipratropium bromide(?????)
  • 1. Relieve bronchospasm by inhalation
  • 2. Uses chronic obstructive pulmonary disease,
    bronchial asthma
  • 3. ganglionic block action stronger than atropine
  • 4. low BBB permeability

116
  • Tertiary amines(???)
  • Mydriatics
  • Anticholinergic in CNS
  • Antispasmatic agents
  • Benactyzine (????,???)
  • 1. Relieve smooth muscle spasm
  • 2. Antianxiety effect

117
Selective M1 Antagonists
  • Pirenzepine(????)
  • Telenzepine(????)
  • Inhibit secretion of gastric acid
  • Clinical use peptic ulcer
  • Not into CNS

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???? ?? ??
N1?? N2?? M1?? M2?? M3?? ??? ????? ??? ??? ??? ??? ?? ??? ???? ????? ?????? ????? ???????????? ??????,???? ?????? ????? ?? ????
120
???? ?? ??
?1?? ?2?? ?1?? ?2?? ?3?? ????? ????????? ?? ????? ?? ????? ????? ??? ???? ?? ??????? ??? ?? ???? ?? ?? ????? ?? ????? ??????? ?? ?? ?????????? ?? ?????? ?? ????? ????
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