Академический Документы
Профессиональный Документы
Культура Документы
Na +
Precursors
(choline/tyrosine)
Synaptic
Precursor cleft
Neurotransmitter
Pre-synaptic Storage
nerve cell Release
Recognition
Ca 2+ by receptors
Metabolic
disposition Post-synaptic
nerve cell
Reuptake
Strategies for Pharmacological Intervention:
Block synthesis and storage: -usually rate-limiting steps; produce long-term effects
Block release: -rapid action and effective
Block reuptake: -increases synaptic neurotransmitter concentrations
Antagonist: (1) A receptor-specific blocker. (2) A molecule, such as a drug (e.g., enzyme
inhibitor) or a physiologic agent (e.g., hormone), that diminishes or prevents the action of
another molecule.
Mode of Action:
Direct-acting: Molecule that physically binds to the target for its effect.
Example: carbachol activates cholinergic receptors,atropine blocks them
Mode of action and agonism are different concepts. For example, a direct-
acting molecule can be either agonistic or antagonistic.
Otto Loewi (Nobel Laureate, 1936)
He also found that atropine can prevent the inhibitory action, but not the
release, of Vagus stoff.
Choline Acetylcholine O
CH3 CH3
Choline CH3 N + -CH2CH2O- CCH3
CH3 N + CH2CH2OH acetyltransferase
CH3
CH3 + +
O
CoASCCH3 CoA-SH
Acetyl-CoA CoA
(from mitochodria)
Synthesis, storage and release of acetylcholine:
Na+
Choline
(10 M)
Choline
Ac-CoA ChAT Synaptic
cleft
Antiporter
Ach
Nerve Ach choline
impulse Ach+ acetic acid
Ach Ach
NN
Pre-synaptic Ca2+Ach AchE
cell
Recognition
Ca2+ by receptors
NM
CAT = choline acetyltransferase Post-synaptic
AchE
AchE = acetylcholinesterase cell
Degradation of acetylcholine:
H2O
: Stimulatory
Synthesis : Inhibitory
Cholinergic antagonists Solid: Agonistic
Dotted: Antagonistic
Atropine (anti-M)
d-tubocurarine Storage Vesamicol
(anti-NM)
Trimethophan
(anti-NN)
Release Botulinum toxin
Cholinergic agonists
(direct acting) AntiChE
Carbachol Ach Reversible (neostigmine)
Pilocarpine
Irreversible (organo-
Receptor Degradation phosphate)
+ action by AchE
An example of indirect agonism:
1
3 CH2 HO CH2
TH
HC COOH HC COOH Dopa decarboxylase
Phenylethanolamine-
HO HO
(L-amino acid
NH2 NH2
N-methyl transferase Tyrosine DOPA decarboxylase)
OH DD (L-AAD)
OH
HO
CH
HO CH2
HO CH PNMT
CH2 DBH CH2
CH2 HO
HO
HO
NH2 NH2
NHCH3
Dopamine
Epinephrine Adrenal medulla Norepinephrine
Dopamine -hydroxylase
Regulation of Norepinephrine Synthesis, Release and Metabolism:
Na+
Tyrosine
Tyrosine R
TH
Dopamine
Signal Dopa DD (DA)
DBH NE Uptake-1
ATP
NE
(-)
R
DBH Post-synaptic
Pre-synaptic Ca2+ NE
ATP
NE
NE
Cellular messengers
R
and effects
CO
M T
Ca 2+
: Stimulatory Tyrosine
: Inhibitory
Solid: Agonistic (Rate-limiting) TH Metyrosine
Dotted: Antagonistic
DopaDA
Reserpine
Adrenergic antagonists
Vesicle (DANE)
Phentolamine (-blocker)
Propranolol (-blocker) Amphetamine, tyramine,
ephedrine
Release
Adrenergic agonists Bretylium, guanethidine
(direct acting)
Cocaine
Isoproterenol Tricyclic antidepressants
Albuterol NE (e.g. imipramine)
Receptor Recapture
+ action by Uptake-1
Autonomic nervous system:
1, 2( G protein coupled)
Adrenergic R
(all G protein 1, 2,
coupled)
Cranial Effectors
Ach Ach
Sympathetic
Sweat glands
Nicotinic Muscarinic
Ach D
Sympathetic Renal vascular
Nicotinic Dopaminergic smooth muscle
(D1)
Ach
Sympathetic (adrenal medulla)
Epi,NE Released into
Nicotinic blood
Sacral
Ach
Motor (somatic) Skeletal muscle
Nicotinic
Gq Gi Gs
Agonist Agonist
Beta1 receptor Alpha2 receptor(Gi)
(Gs)
AC
s i
s i
Gs = stimulatory G protein
Gi = inhibitory G protein
AC = adenylyl cyclase (converts ATP to cAMP which gives the effect)
Distribution & functions of adrenergic receptors:
1: postsynaptic effector cells, especially smooth muscle
Vasoconstriction, hepatic glycogenolysis
3 1 CH HO CH2
2
TH HC COOH
HC COOH HO
HO
Phenylethanolamine- NH2
NH2 DOPA
N-methyl transferase Dopa decarboxylase
Tyrosine
DD (L-AAD) (L-amino acid
OH OH
decarboxylase)
HO CH HO CH
PNMT DBH HO CH2
CH2 CH2
HO HO
HO CH2
NHCH3 NH2
NH2
Dopamine
Gs Gi
Nicotiana tabacum
(cultivated tobacco)
- an Ionotropic Receptor
Competitive Depolarizing
Physically blocks Binds and locks the receptor
Ach binding open
INHIBITOR
Cholinergic receptors: Muscarinic
Muscarinic actions -- reproduced by injection of
muscarine, from Amanita muscaria (mushroom).
Similar to those of parasympathetic stimulation
Multiple muscarinic cholinergic receptors
distributed in different tissues. Therefore, the
muscarinic actions are dependent on the
receptor types in different tissues and cells.
Neural/enteric (M1): CNS, ENS, gastric parietal cells (excitatory; Gq)
Cardiac (M2): atria & conducting tissue; presynaptic (inhibitory; Gi)
Glandular/endothelial (M3): exocrine glands, vessels (excitatory; Gq)
Neural (M4): CNS (inhibitory; Gi)
Neural (M5): CNS (excitatory; Gq)
(Sites of primary expression are listed; all are found in CNS)
Muscarinic acetylcholine receptors
G Protein-Coupled Receptors (Metabotropic Receptors)
M1(enteric,neural) M2(cardiac)
M3(glandular,vascular) M4(CNS)
Agonist Agonist
M5(CNS)
Gq Gi
Mostly excitatory cAMP
CNS excitation Mostly inhibitory Ca2+ channel
IP3, DAG Gastric acid secretion Cardiac inhibition (Inhibition)
Gastrointestinal motility Postsynaptic
Intracellular Ca2+ inhibition K+ conductance
(Stimulation) Glandular secretion Neuronal inhibition (Slow IPSP)
Contraction of visceral
K+ conductance smooth muscle
(Depolarization) Vasodilation (via NO)
Clinical manifestation of excessive cholinergic effects
(DUMBELS)
D Defecation
U Urination
M Miosis
B Bradycardia
E Emesis
L Lacrimation
S Salivation
Effects of muscarinic antagonists:
DRY AS A BONE, RED AS A BEET, MAD AS A
HATTER.
Decreased sweating, salivation and lacrimation
Reflex peripheral (cutaneous) vasodilation to
dissipate heat (hyperthermia)
CNS effects of muscarinic inhibition --
restlessness, delerium, hallucination
ALSO:
Bronchodilation
Tachycardia
Mydriasis (pupil dilation) and Cycloplegia (loss of focus)
GI and bladder atony leading to urine retension
Physiological Effects of ANS
Stimulation and Inhibition
Receptor distribution and effects in the autonomic nervous system:
Fat Lipolysis
From: Rang et al. Pharmacology, 6th Ed. p. 169. Also, see Katzung, Basic & Clinical Pharmacology, 10th Ed. p.86.
Cardiovascular Pharmacology
(Blood Pressure)
Cardiovascular effects of IV infusion of epinephrine, norepinephrine,& isoproterenol in man:
Norepinephrine (predominantly -agonist) causes vasoconstriction and increased systolic
and diastolic BP, with a reflex bradycardia.
Isoproterenol (-agonist) is a vasodilator, but strongly increases cardiac force and rate.Mean
arterial pressure falls.
Epinephrine combines both actions,since it stimulates both receptors equally).
Sir Henry Hallett Dale
(Nobel laureate, 1936)
(Arterial pressure of an
anesthetized cat was
Two kinds of effects produced by Ach. measured)
A. Ach causes a fall in BP due to vasodilation.
B. A larger dose of Ach also produces bradycardia, further reducing BP.
C. Atropine blocks the effect of Ach in lowering BP.
D. Still under the influence of atropine, a much larger dose of Ach causes a rise in BP& tachycardia.
A, B: Muscarinic effects of Ach (M3, M2)
C: Muscarinic antagonistic effect (M)
D. Stimulation of sympathetic ganglia (NN)
Mechanism of action of Ach
Ach modifies organ function by two mechanisms:
-Ach released from parasympathetic nerves binds to
muscarinic receptors on effector cells and alter their
function.
-Released Ach binds to muscarinic receptors on nerve
terminals and inhibits release of neurotransmitters.
All muscarinic receptors are G protein coupled
Binding of muscarinic agonists to receptors activates IP3
and DAG cascade.
DAG opens smooth muscle calcium ions channels.
IP3 releases Ca++ from endoplasmic & sarcoplasmic
reticulum.
Muscarinic agonists increase cellular cGMP concentration
Activation of muscarinic receptors also increases potassium
flux across cardiac cell membranes and decreases it in ganglia
and smooth muscle cells.This effect is mediated by the
binding of an activated G protein subunit to the channel
Muscarinic agonists attenuate activation of adenylylcyclase
and decrease cAMP levels,this reduces physiological response
to stimulatory hormones
Cholinergic action(molecular mechanisms):
Intracellular signalling triggered by Ach in smooth muscle
(contraction) main players:m3,Gq,PLC,IP3,DAG,Ca++
Nitric oxide (NO) signaling pathway for SMC relaxation
Second
messenger
Sildenafil (Viagra)
is an inhibitor for
PDE 5.
Intracellular signalling triggered by Ach in heart muscle: results in
bradycardia. Main molecular players: M2, Gi, adenylylcyclase
Pulmonary Pharmacology
(Asthma and COPD)
Ocular Pharmacology
(Glaucoma)
Cholinergic effects: Adrenergic effects:
Contraction of pupillary constrictor muscle Contraction of pupillary dilator muscle
-- miosis -- mydriasis
Contraction of ciliary muscle - bulge of lens Stimulation of ciliary epithelium
-- near vision, outflow of aqueous humor -- production of aqueous humor
Pupillary dilator muscle ()
Pupillary constrictor muscle
(M3)
Trabecular meshwork
(opened by pilocarpine)
Lens
(M3)
Secretion of aqueous humor ()