Autonomic Pharmacology

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Chapter 3 Autonomic Pharmacology

The autonomic nervous system (ANS) is so named because it is autonomous; it functions independently of the conscious or somatic nervous system. For example, you do not need to consciously tell your heart to beat faster when you exercise or your digestive tract to increase activity after eating. However, the ANS can be influenced by conscious thought; a classic example was demonstrated by the experiment on Pavlov’s dog, which salivated at the sound of a bell because the bell had been rung before every meal, so the dog had learned to associate the bell with meals.

To understand autonomic function, and by extension to understand how to manipulate the ANS, you will need to understand how the two types of the ANS coexist and function, how each system exerts its effects, and finally what pharmacologic mechanisms exist to increase or decrease each component of the ANS. Memorization of the receptors, their distribution, and their effects is mandatory for achieving this goal and will enable you to accurately predict effects and side effects of drugs (Table 3-1).

TABLE 3-1 Autonomic Receptors: Function and Distribution

Receptor	Function	Distribution
Sympathetic
α₁	Constriction of smooth muscles	Blood vessels and piloerectors in skin (vasoconstriction and goose bumps) Sphincters (bladder, gastrointestinal [GI]) Uterus and prostate (contraction) Eye (contraction of the radial muscle = pupillary dilation/mydriasis)

α₂ Inhibition of sympathetic autonomic ganglia (decreases the sympathetic nervous system [SNS])

Presynaptic ganglionic neurons

GI tract (less important pharmacologically, included for completeness)

β₁ Increase cardiac performance and liberation of energy

Heart, the most important for β₁; (increased heart rate, contractility, conduction speed)

Fat cells (release fat for energy via lipolysis)

Kidney (release renin to conserve water)

β₂ Relaxation of smooth muscles and liberation of energy

Lungs (bronchodilation)

Blood vessels in muscles (vasodilation)

Uterus (uterine relaxation)

GI (intestinal relaxation)

Bladder (bladder relaxation)

Liver (to liberate glucose via glycogenolysis)

Parasympathetic N (Nicotinic) ”Nerve to nerve” and ”nerve to muscle” communication

Sympathetic and parasympathetic ganglia

Neuromuscular junction (NMJ)

M (Muscarinic) To oppose most sympathetic actions at the level of the organs

Lung (bronchoconstriction)

Heart (slower rate, decreased conduction, decreased contractility)

Sphincters of GI and bladder (relax)

Bladder (constriction)

GI (intestinal contraction)

Eye (contraction of the circular muscle = pupillary constriction or meiosis)

Eye (contraction of the ciliary muscle = focus for near vision)

Glands: lacrimal, salivary, bronchial (secretion)

Special Notes

There is no parasympathetic innervation of blood vessels.

Sweat glands are innervated by sympathetic nerves, but paradoxically use M receptors.

Sexual arousal is parasympathetic, but orgasm is sympathetic.

The ANS has two parts:

The sympathetic nervous system (SNS)

• The SNS is the fight-or-flight response. The term sympathetic means supportive, and the SNS is designed to support survival during times of stress.

The parasympathetic nervous system (PNS)

• The PNS usually causes the opposite effect from that of the SNS. Para means beside, and the parasympathetic system works alongside the sympathetic system to help keep it in balance.

As a primer to help you remember the fight-or-flight response, consider a caveman who requires an intact SNS to stay alive. While he is fighting with (or maybe running away from) a saber-toothed tiger, what physiologic effects would promote his survival?

Dilated eyes to see better

Quiet digestive processes to save energy (dry mouth and inactive digestive tract)

Availability and liberation of energy (glucose production)

Increased cardiac performance (faster heart rate, faster conduction, stronger contractions)

Increased respiratory performance (dry, dilated airways)

Sweating to cool off

Piloerection to make the hair on the arms stand up and make one look bigger

Bladder control

The PNS, to keep everything in balance, would therefore oppose all these effects. If you remember the flight-or-fight response and think of the opposite of the fight-or-flight response, you will remember the majority of the important ANS functions.

Autonomic Anatomy

Parasympathetic nerves are arranged in a craniosacral distribution. They:

Follow cranial nerves III, VII, IX, and X (X is the vagus nerve)

The vagus nerve is the most important parasympathetic nerve.

Also follow splanchnic nerves, which arise from sacral nerves

The sympathetic nerves primarily arise from the thoracic and lumbar spinal roots.

Therefore the parasympathetics anatomically originate from the top and bottom of the brain and spinal cord, and the sympathetics are in the middle of the spinal cord.

Ganglia and Neurotransmitters

For both the sympathetic and parasympathetic systems, the autonomic nerves exit the brain or spinal cord and then enter a relay station called a ganglion. The function of the ganglia is to transfer (and sometimes modify) the signals from the presynaptic neuron to the postsynaptic neuron. The neurotransmitter for both the SNS and PNS ganglia is acetylcholine (ACh).

The postsynaptic neuron then innervates an organ. If the neuron is a sympathetic neuron, then the neurotransmitter will be norepinephrine (NE). If the neuron is a parasympathetic neuron, then the neurotransmitter will be acetylcholine.

The parasympathetic ganglia are located close to the organs that they innervate. Some examples include the ciliary, pterygopalatine, submandibular, otic, and pelvic ganglia.

This is in contrast to sympathetic ganglia, which are located in the sympathetic chain that runs alongside the spinal column and are located at a distance from the organs. They are described as the “paravertebral (beside) and prevertebral (in front of) sympathetic chains, depending on their physical relationship to the vertebral column (Figure 3-1).

Figure 3-1 Ganglia and neurotransmitters.

ACh is the “preganglionic nerve to postganglionic nerve” transmitter in the ganglia for both the sympathetic and parasympathetic systems. Only special drugs manipulate the ganglia. It would be logical to assume that drugs that influence ACh would have a strong influence on ganglia, but they do not.

ACh is the “postganglionic nerve to organ” neurotransmitter for the parasympathetic system, and NE is the transmitter for the sympathetic system. It is important to understand this difference, because drugs that focus on ACh will manipulate the parasympathetic system, whereas drugs that manipulate effects related to NE will manipulate the sympathetic system.

Special Cases

The sympathetic innervation of the adrenal gland is direct from the spinal cord and uses ACh as the neurotransmitter. The adrenal gland functions as a special form of ganglion that secretes epinephrine directly into the bloodstream.

Another special case is the innervation of sweat glands. They are sympathetically innervated, but the postsynaptic nerve releases ACh instead of NE.

Autonomic Receptors

ACh binds to muscarinic and nicotinic receptors, abbreviated M and N.

M receptors are on organs that receive parasympathetic innervations.

N receptors are in ANS ganglia and function as nerve to nerve neurotransmitters. N receptors are also important in nerve to muscle communication (the neuromuscular junction).

NE (and epinephrine) bind to alpha and beta receptors (α and β). Another name for epinephrine is adrenaline, so these receptors are also commonly referred to as adrenergic receptors.

Subtypes of these receptors exist, such as M₁, M₂, M₃, α₁, α₂, β₁, and β₂. Even more subtype classifications exist than are listed here, but not all of them are clinically important.

The receptor types that are clinically important include M, N, α₁, α₂, β₁, and β₂. You must know the distribution and function of these receptors in the body to understand and predict the effects of drugs that influence the ANS (see Table 3-1).

Important, autonomic receptors also exist in many parts of the body but function in a way unrelated to the ANS. Some examples include:

Nicotine receptors in the addiction pathway

Adrenergic receptors in the brain, related to mood

Muscarinic receptors in the brain, involved in Parkinson’s disease and related movement disorders

Manipulating the Autonomic Nervous System

The ANS consists of two systems: the SNS and the PNS. Most of the time, each system is opposing the other. Therefore to change this balance, we can strengthen one system or weaken the other.

↑ Parasympathetic:

Increase stimulation of the M receptors

• Give an agonist (vagotonic: the vagus nerve is the primary PNS nerve, hence the name “vago”).

• Inhibit the breakdown or removal of endogenous (the body’s own) ACh.

↓ Parasympathetic:

Decrease M receptor stimulation

• Give an antagonist (vagolytic).

↑ Sympathetic:

Increase stimulation of the α and β receptors via:

• Administration of an agonist (sympathomimetic) that stimulates these receptors

• Inhibition of the breakdown or removal of endogenous NE or epinephrine

• Inhibition of synaptic NE reuptake by the presynaptic cell, leading to increased NE in the synaptic cleft

↓ Sympathetic:

Decrease stimulation of the α and β receptors

• Give an antagonist (sympatholytic) that blocks these receptors.

• Give a drug to turn down the ganglion (relay station).

Ganglionic Pharmacology

An additional mechanism of manipulating the ANS is through drugs that affect the autonomic ganglia. They can be ganglionic stimulants or ganglionic blockers. Most of these drugs are no longer used clinically and are of historical importance only, because drugs that target the ganglia usually have a broad range of effects and therefore many side effects; more directed, specifically acting drugs that do not act on the ganglia are now available and have replaced them. Some examples of these older ganglion-acting drugs include: guanethidine, hexamethonium, and mecamylamine.

Nicotine is a clinically important agent that influences activity of the autonomic ganglia. As would be suggested by the name, nicotine is an agonist of nicotine receptors and is best known as a component of tobacco products and for its role in addiction. The major action of nicotine consists initially of transient stimulation, followed by a more persistent depression of all autonomic ganglia. Effects of nicotine are similar to increasing the effects of the SNS, including increased blood pressure and heart rate. In addition, nicotine is strongly associated with the pathways in the brain responsible for reward and addiction.

Parasympathetic Drugs

Handling of Acetylcholine

ACh is stored in vesicles in the terminal portions of the nerves. It is released when an action potential (AP) is conducted through the neuron. The presynaptic AP opens up Ca channels and allows Ca to enter the neuron. Ca causes binding of the ACh vesicles to the presynaptic membrane. ACh is then released into the synaptic cleft. In the synaptic cleft, ACh binds to M or N receptors (depending on the type of synapse and which receptors are present).

ACh has three fates once it has entered the synaptic cleft:

1 It is broken down by acetylcholinesterase (the most important of the three).

2 It is taken back (reuptake) into the presynaptic neuron.

3 It diffuses away out of the synaptic cleft.

Manipulating the Parasympathetic Nervous System

There are three ways to manipulate the PNS:

1 Administering a muscarinic agonist (increases PNS activity)

2 Administering a muscarinic antagonist (decreases PNS activity)

3 Administering a cholinesterase inhibitor, which results in an increase of ACh in the synaptic cleft (increases PNS activity)

Common muscarinic agonists include:

Muscarine (the prototype, but not a clinically used drug)

Common muscarinic antagonists, which are also called anticholinergics, antimuscarinics, and vagolytics, include:

Atropine (the prototype and widely used clinically)

• Benztropine

• Glycopyrrolate

• Ipratropium (inhaled only)

• Tolteridine

• Scopolamine

Common cholinesterase inhibitors include:

Echothiophate (eye drops only)

Insecticides (malathion, parathion) and chemical warfare (sarin)

Effects of These Drugs

Instead of memorizing the effects of the individual drugs, it is better to learn the distribution of the receptors of the SNS and PNS and then, by logic, determine what the effects of the drugs would be (see Table 3-1). These drugs will have effects on the desired target organ but also have effects on other unintended target organs (which will cause side effects).

Main Clinical Uses of Muscarinic Agonists

Constrict the pupil

Promote salivation

Main Clinical Uses of Cholinesterase Inhibitors (Also Known as Anticholinesterases)

The primary indication for cholinesterase inhibitors is to increase levels of ACh in the neuromuscular junction. This increases muscle strength in conditions in which there is a problem with the nicotinic receptor on the muscle. Clinical uses include the following:

Treating myasthenia gravis

Reversing neuromuscular blocking drugs used for anesthesia

Some Drugs with (Unwanted) Anticholinergic Side Effects

Tricyclic antidepressants

Sympathetic Drugs

The synthesis of adrenergics follows the pathway below (adrenergic means pertaining to systems that respond to adrenalin). Note that adrenalin and epinephrine are the same molecule, as are noradrenalin and NE:

Note that the addition of the hydroxyl (OH) group is called hydroxylation, and the removal of the methyl (CH₃) group is called demethylation.

The nor in norepinephrine refers to no radical (no CH₃ group), compared with epinephrine.

Manipulating the Sympathetic Nervous System

Manipulating the SNS is a little simpler than manipulating the PNS.

You can give an agonist:

For α receptors

For β receptors

You can give an antagonist:

For α receptors

For β receptors

Fine print: You can give drugs that prevent release of NE from presynaptic nerve endings with ganglion blockers. This will result in a decrease of ganglionic transmission and result in decreased SNS activity. However, these drugs are used less and less commonly because of side effects.

Fine print #2: Some drugs are inhibitors of enzymes that degrade adrenergic molecules. These drugs (catechol-O-methyltransferase [COMT] inhibitors and monoamine oxidase [MAO] inhibitors used for Parkinson’s disease and depression) are designed to influence the adrenergic transmitter levels in the brain but are not intended to affect changes in the SNS. However, they can result in some systemic SNS changes.

Some adrenergic drugs are selective for a given receptor, but most of the drugs bind to and interact with multiple receptors (even if they are described as acting on only one receptor). For example, β₁ selective drugs will also bind β₂ receptors, and vice versa.

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Applied Pharmacology