Download Muscarinic AChR agonist

Clinical Pharmacology
Autonomic pharmacology
Jane M Johnston Ph.D.
Efferent (motor) nerves
 Two systems
 Autonomic

nerves (unconscious)
Eg cardiac output, respiration, etc
 Somatic
nerves (voluntary)
ANS branches
 cholinergic fibres - acetylcholine
 adrenergic fibres noradrenaline (norepinepherine
NE)
Functions and origins of the ANS
Action of ANS drugs
 Drugs to block ANS chemical
transmission
 Drugs to mimic ANS action
 ANS drugs can modify a variety of
effector tissues
 Cardiac
muscle
 Blood pressure
 Exocrine glands
Cholinergic transmission
 Acetylcholine is at motor neuron and CNS
nerve terminals
 Synthesized from



Acetyl coA (mitochondria)
Choline (dietary)
Catalyzed by choline acetyl transferase (ChAT)
 Release is dependent on Calcium (Ca2+)
 Causes muscle contraction
Acetylcholine
 Identified 1921
 Present at all NMJ and also CNS
 Synthesized in the axon terminal
 Diffuses across synaptic cleft
 Two receptor subtypes
 Nicotinic ACh
receptors
 Muscarinic ACh receptors
The discovery of vagusstoff
E.Chudler 2001
Neuromuscular Junction
Synaptic End Plate
1999 Sinauer Associates Inc
T.Caceri Veterinary Histology 2003
Acetylcholine and NMJ
Characteristics of a
neurotransmitter
 Synthesized in (or transported to)
presynaptic terminal
 Stored in vesicles
 Regulated release
 Receptor located on postsynaptic
membrane
 Termination of action
Synaptic vesicles at the NMJ (EM)
Heuser and Heuser
Synthesis and release of
neurotransmitters
Synaptic Transmission in: Basic Neurochemistry 6th Edition
Presynaptic events
 Calcium influx releases synaptic
vesicles from microtubules
 Movement of synaptic vesicles to
sites of action
 Interaction of specific proteins
 Vesicle docking
 Membrane fusion
 Calcium dependent exocytosis
Fusion proteins regulate
neurotransmitter release
 Vesicle proteins
 Synaptobrevin
 Presynaptic membrane proteins
 Syntaxins
 SNAP-25
The SNARE hypothesis
SNARE (Soluble
N’ethylmalemide
sensitive fusion
Attachment
protein
REceptor)
A. Pestronk www.neuro.wustl.edu/neuromuscular 2003
Many presynaptic proteins
regulate neurotransmitter release
Synaptic Transmission in: Basic Neurochemistry 6 th Edition
Vesicular transport of NT – drug
implications
 Toxins targeting neurotransmitter
release
 Spider
venom (excess ACh release)
 Botulinum (blocks ACh release)
 Tetanus
Postsynaptic events
 Boutons have multiple nerve terminals
 Simultaneous release
 Stimulation of contraction via AP
 Acetylcholine degraded after action
 ACETYLCHOLINESTERASE
(AChE)
Motor
neuron
innervating
skeletal
muscle
Cholinergic receptors
 Two classes for acetylcholine
 Nicotinic and muscarinic
 Nicotinic
are ion channels
Ionotrophic
 Muscarinic are G-protein coupled
Metabotrophic
Nicotinic AChR are sodium
channels
1999 Sinauer Associates Inc
Ionotropic AChR
 Consist of five polypeptide
subunits
 Receptors vary in:

subunit structure
 agonist sensitivity
 distribution
 Mediate fast synaptic
transmission
Muscarinic AChR activate Gproteins
1999 Sinauer Associates Inc
Metabotropic AChR
 Five muscarinic AChR subtypes
 G protein coupled
 Slower synaptic transmission
via intracellular signaling
cascade
Mode of cholinergic drug
action
 Cholinomimetics
 agonist
 antagonist
 Cholinesterase inhibitors
 Clinical applications
Cholinomimetics
Katzung, 2001
AChR agonists and antagonists
 Nicotinic AChR agonists
 Nicotine
 Nicotinic AChR antagonists
 Strychnine
 Snake toxins
 Bungarotoxin
 Muscarinic AChR agonist
 Muscarine
 Muscarinic AChR antagonists
 Atropine
Cholinesterase inhibitors
 Inhibit breakdown of acetylcholine at
the synapse
 Act by
 Binding
to acetylcholine esterase (steric
hinderance or hydrolysis)
 Actions of acetylcholine persist at synapse
 Pesticides and nerve gases
Clinical Implications
 Myasthenia Gravis
 Glaucoma
 Cholinergic poisons
 CNS –
 Alzheimer’s
Disease
 Schizophrenia
Myasthenia gravis
 Affects skeletal muscle at NMJ
 Involves autoimmunity to nicotinic
receptors
 Extreme weakness, difficulty
speaking, eating, breathing
 Cholinesterase inhibitors for therapy
Adrenergic transmission
 Catecholamines are the neuroTs
 Complex synthesis
 Secretion at nerve terminals and adrenal
glands
 Adrenal glands


Two adrenal glands
Consist of cortex (outer) medulla (inner)
medulla secretes:


Epinephrine (adrenaline)
Norepinephrine
NE and E are
released at
nerve
terminals
and secreted
by the
adrenal
medulla
Norepinephrine and epinephrine
 Catecholamines
 Synthesized from dopamine
 Present in CNS and sympathetic
nerves
 Widely distributed, general
behavioral arousal eg raise blood
pressure etc
 Stress increases release of
norepinephrine
Synthesis of norepinephrine (NA)
Synthesis of epinephrine
(adrenaline)
Adrenergic receptors
 Four receptor subtypes
 a1,
a2, b1, b2
 G protein linked
 Bind
either norepinephrine or epinephrine
Sympathetomimetic drugs
 Can act directly or indirectly
 Direct binding to receptors
 Epinepherine, dopamine (CNS and renal)
 Indirectly
 Drugs targeting synthesis and release of NE and
NA eg DBH inhibitors, reserpine - depletes stores
 Drugs targeting reuptake at synapse eg cocaine,
Tricyclic antidepressants
Importance of sympathetomimetic
drugs
 Cardiovascular system
 Regulation of smooth muscle affects heart and
blood pressure

beta blockers
 Respiratory tract
 Smooth muscle relaxation – bronchodilation

Isoproterenol, albuterol (asthma)
 Metabolic effects
 Liver effects, insulin secretion
 CNS
 Nervousness, emotional well-being, psychosis etc