Autonomic Pharmacology

Langley originally defined the autonomic nervous system (s/a ANS) as consisting as nerve cells and fibers by which efferent impulses pass to tissues other than skeletal muscle. So ANS is motor system controlling visceral organs for homeostasis. There is a sensory component of ANS. Sensory nerves innervating viscera are part of ANS. Sensory components establish reflex loops for smooth control of ANS (ex. baro and chemoreceptor reflexes).

In bifurcation of common carotid artery, there is a region of thinning of common carotid (this region pulses when you squeeze it) that is richly innervated by autonomic fibers from petrosal ganglion at neck. When blood pressure goes up, these sensory nerves activate. This is a bipolar neuron: one pole -> in carotid sinus and other pole in dorsal medulla. Brain processes information and send efferent impulse to heart slowing heart and reducing contractility letting blood pressure go down. If heart go down too much, sympathetic reflex speeds it up.

They sense O2 levels in blood. CO2 levels go up. CO2 go to dorsal medial medulla. Brain tells lung to breathe fast.

Baroreceptor reflex maintains blood pressure in narrow range.

Chemoreceptor reflex maintain O2 levels.

Drugs can elicit direct and reflexive effects on body.

Afferent and efferent components that mediate reflex loops.

4. Variety of metabolic processes including release of catecholamines, glucagon, insulin, and others.

1. Sympathetic

2. Parasympathetic

Parasympathetic neurons are in brain (medulla) and sacral spinal cord.

Sympathetic neurons are in the thoracolumbar spinal cord.

All autonomic preganglionic neurons make synapses with clusters of neurons called ganglia.

The spinal cord has grey matter and white matter.

The spinal cord has the intermedial lateral cell column which has the origin of sympathetic preganglionic neurons which send axons through ventral root where they synapse on a ganglion. The ganglionic neurons send out postganglionic neuron to target cell (i.e. a visceral organ like the heart). The ganglion are found in a chain of ganglion that is close to spinal cord in paravertebral ganglionic chain. Sympathetic system has short preganglionics and long post ganglionic axons.

When this axon comes out spinal cord, it goes up and down the chain to synapse on adjacent ganglion so have diffusion effect so one preganglionic neuron can stimulate neuron in multiple ganglion. Have collateralization of terminals in ganglion so one can stimulate many ganglia giving global discharge of sympathetic system -> this is useful for fight or flight.

Long presynaptic acetylcholine fiber comes off of brain. Short postsynaptic with nicotinic receptor goes to target organ.

So the preganglionic neuron is long and the postganglionic neuron is short. The postganglionic neuron is usually on surface of innervated organ.

Activity of parasympathetic nervous system give discrete activation of specific organ (not a global effect). Ganglia not only relay stations, but serve as integrated areas. Have multiple ganglia on heart (not just one). Different ganglia control aspects of cardiac function through different pathways: one controls cardiac rate, one controls AV conduction, and one controls myocardial contractility.

This includes the sympathetic and parasympathetic systems.

Major sensory neurons are found in the dorsal root ganglia. They are not as well understood as efferent component. They utilize different neurotransmitter.

With respect to preganglionic neuron (be it parasympathetic or sympathetic), it will release acetylcholine (s/a Ach) and the receptor effected is nicotinic.

In sympathetic nervous system, postganglionic neuron has norepinephrine and receptor that is activated depends on target system ( and receptors). In heart, have receptor.

In parasympathetic nervous system, parasympathetic postganglionic releases acetylcholine as does its preganglionics. This acetylcholine of the postganglionic influences a muscarinic receptor.

The sensory neurons have variety of neuropeptides (a dozen have been identified). An example is substance P. Substance P is probably a neurotransmitter contained in sensory neurons that mediate sensation of pain. Pain is carried by unmyelinated sensory neurons that release substance P to dorsal root of spinal cord.

Langley and Levondosky noted effect of ingestion of extract of adrenal gland and excitation of sympathetic nerve. The sympathetic nervous system therefore releases epinephrine like compound. The compound was its demethylated analog called NorEp.

Langley postulated excitation or inhibition receptor substance on tissues. The response he saw after injection of adrenal extract depended on receptor. Injection of muscarine -> gave effect similar to stimulating parasympathetic system. So vagus nerve release muscarinic like substance called acetylcholine.

Otto Loewi -> he demonstrated chemical transmission in CNS. He had frog vagus and heart. When stimulate vagus, heart rate goes down. He put bathing medium of first heart and put it on another heart making that heart beat go down. The bathing medium had Ach.

((In ANS and CNS -> they contain NorEp and Ach, they are cholinergic, adrenergic)).

It is found neurons have multiple neurotransmitters (NT).

In sympathetic system, norepinephrine (NorEp) is commonly cofound with neuropeptide y (NPY). Stimulation of sympathetic nerves causes vasoconstriction. NPY is a more potent vasoconstrictor than NorEp.

Cholinergic neurons have VIP (vasoactive intestinal polypeptide).

These multiple transmitters -> one transmitter modulate action of other compound released.

Adrenergic -> to release adrenalin. Neuron with catecholamine (NorEP) is adrenergic (or noradrenergic).

On parasympathetic side, nerve with Ach and releases Ach would be cholinergic.

Tissue responsive to neurotransmitter is called adrenoreceptive or cholinoreceptive (they are activated or inhibited by NorEp or Ach).

Sympathomimetic drugs -> drugs where action mimic turning on sympathetic nervous system.

Parasympathomimetic drugs (s/a cholinomimetic) -> drugs that mimic effect of turning on parasympathetic nervous system.

Opposite of mimicry is block effect.

Sympatholytic -> they inhibit action of sympathetic nervous system.

Parasympatholytic -> inhibits action of parasympathetic nervous system.

All autonomic preganglionic neurons activate nicotinic receptors. Nicotinic receptors on autonomic ganglion is on neuron. Nn is nicotinic receptor on neuron. Nm is nicotinic receptor is on voluntary muscle cell.

Postganglionic parasympathetic activate muscarinic receptors.

Postganglionic sympathetic neuron activate adrenergic receptors ( and ).

Lists receptor on organ and what happens when you turn it on. Pay attention to receptor of eye, heart, blood vessels, lungs, intestines, bladders, sex organs, adrenal medulla, liver, pancreas, fat cells, and everything else).

blocker -> receptor on vascular smooth muscle. Turn it on gives vasoconstriction. Block it gives vasodilation.

It regulates activities not considered under voluntary control and function below the level of consciousness. Examples of these activities are respiration, circulation, digestion, body temperature, metabolism, sweating, and secretion of certain endocrine glands.

ANS maintain constant internal environment to maintain homeostasis. In most cases, sympathetics and parasympathetics act as physiological antagonist.

(Heart: Sympathetic accelerate cardiac rate. Parasympathetic diminishes cardiac rate).

(Eye: Sympathetics open pupil. Parasympathetics close pupil).

Most viscera innervated by both divisions of ANS. Level of activity in any given organ represent effect of activation of parasympathetics and sympathetics effects on organ.

Physiological antagonist effect may occur by action on same cell.

In heart and intestine, sympathetics and parasympathetics act on same effector cell for antagonist response.

In eye, sympathetics act by controlling radial muscle of eye. If contract radial muscle pupil get larger.

Parasympathetics affect different muscle (sphincter muscle). If contract sphincter muscles pupil get smaller.

Parasympathetics gives copious watery salivary secretion. Sympathetic activation gives thick viscous secretion.

Both parasympathetic and sympathetic don't innervate an organ (i.e. blood vessels just get sympathetic activation -> no antagonism is possible).

Sympathetic nervous system is on continuously (i.e. basal tone). It varies minute to minute and from organ to organ.

Sympathoadrenal system often acts as a unit to facilitate fight or flight.

Activation of sympathetic nervous system increases blood pressure, increases heart rate, blood goes to skeletal muscle, blood vessel dilate, pupils dilate, and bronchioles dilate.

In a controlled environment and in the absence of stress, sympathetics not needed for life. In chemosympathonectomy (using drugs to destroy sympathetic system), animals do just fine.

It is organized for discrete activation of localized target organ. Its main function is conservation of energy and maintenance of organ function during periods of normal activity. See decrease in heart rate, blood pressure, enhanced GI mobility and secretion, emptying of bladder, and constriction of pupils.

Action potential (AP). Axonal conduction. Membrane potential.

- 70 mV in interior of axon with respect to exterior. High [K+] intracellularly and low Na+ and Cl- intracellularly. Energy requiring ionic pumps maintain concentration. Depolarization -> get permeability of membrane to sodium. See delayed opening of potassium channels and repolarization process propagated down axons. When axon terminal invaded by action potential, Ca++ flows in.

Synaptic vesicles (sacs with neurotransmitter). These sacs go to terminal membrane where they fuse with membrane and contents get ejected. We would predict the membrane would get longer, but some membrane gets pinched off to form new synaptic vesicle.

For ANS neurotransmitters, neurotransmitter synthesized in nerve terminal.

By contrast, the neuropeptide must be synthesized at the perikaryon (cell body) by protein synthesis machinery. These compounds are transmitted down axon to terminal.

The neurotransmitter diffuse down synaptic cleft where they interact with post or pre synaptic receptors.

When transmitter released, to stop process, neurotransmitter can diffuse away in blood stream (get lower concentration of neurotransmitter) or can have metabolic enzyme process (i.e. acetylcholinesterase metabolize Ach).

In case of NorEp, there is an active transport system that brings NorEp back into the cytoplasm of the nerve terminal and there is an active transport system that takes NorEp back into synaptic vesicle.

Diffusion

Degradation

Reuptake

These peptides are degraded by peptidases. No reuptake. Demonstrated they are found in vesicles.

1. Drug can interfere with synthesis of the neurotransmitter.

(hemicholinium, methyl para tyrosine)

For example, on cholinergic side, hemicholinium interferes with synthesis of Ach.

Precursor for biosynthesis of catecholamines is tyrosine (later on it is dopamine). Use structural analog of tyrosine -> methyl para tyrosine -> inhibit biosynthesis of catecholamines on adrenergic side.

2. Metabolic transformation by same pathway of precursor of the neurotransmitter.

(methyl DOPA)

The biosynthetic enzyme of catecholamine aren't substrate specific. So on adrenergic side, methyl DOPA (not DOPA) can be metabolized to methyl dopamine and methyl norepinephrine. Methyl norepinephrine gets released due to action potential, but don't have same activity of endogenous neurotransmitter. So false transmitter blocked effect of sympathetic nervous system.

3. Blockade of neurouptake

(cocaine, tricyclic antidepressants, reserpine)

NorEp gets reuptaken -> drugs can block reuptake. Cocaine blocks NorEp uptake. Tricyclic antidepressant drugs block reuptake of the neurotransmitter.

Active transport process take NorEp from synaptic cleft to cytoplasm. Active transport take NorEp from cytoplasm to synaptic vesicle -> reserpine blocks that active transport process.

4. Other drugs cause release of content at nerve terminal.

(black widow toxin, amphetamine)

Black widow toxin has cholinergicomimetic effect via release of Ach.

Amphetamine is sympathomimetic -> effect by release of catecholamines.

5. Other drugs block release of neurotransmitter.

(botulinum toxin, bretylium)

Botulinum toxin prevents release of Ach.

Drug called bretylium blocks release of NorEp.

6. Lots of drugs mimic effect of endogenous neurotransmitter postsynaptically.

(muscarine, nicotine, phenylepinephrine, clonidine, isoproterenol)

On cholinergic side, muscarine mimics muscarinic effects of Ach. Nicotine mimics nicotinic effects of Ach.

On adrenergic side, variety of receptor types: and .

1 receptor activation is mimicked by drug called phenylepinephrine.

2 receptor activation is mimicked by clonidine.

Isoproterenol mimics either receptor.

7. You can also block effect of neurotransmitter postsynaptically.

(atropine, curare, trimethaphan, phenoxybenzamine, propranolol)

Muscarinic effects of Ach blocked by atropine.

Nicotinic effects of Ach on skeletal muscle blocked by curare.

Nicotinic effects at ganglia blocked by trimethaphan.

On adrenergic side, receptor blocked by phenoxybenzamine.

receptors blocked by propranolol (a nonspecific blocker).

8. Inhibition of enzymatic degradation

(anticholinesterase drugs, monamine oxidase inhibitors)

On cholinergic side, have anticholinesterase drugs.

On adrenergic side, monoamine oxidase inhibitors.