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