clinical pharmacology autonomic pharmacology jane m johnston ph.d
TRANSCRIPT
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
T.Caceri Veterinary Histology 2003
1999 Sinauer Associates Inc
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 6 th 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 G-proteins
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 1, 2, 1, 2
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