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9. Drugs which act on the Autonomic Nervous System
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14th of February, 2010

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The autonomic nervous system, as the name implies, is not under voluntary control. It supplies internal organs, e.g. the stomach, intestine, bronchi (the lungs), heart, blood vessels, sweat glands, bladder and the eyes. Therefore, it controls all sorts of functions – from breathing to sexual activity and from sweating to digestion. It consists of two divisions – sympathetic and parasympathetic. These divisions oppose each other but a careful balance is maintained by special centres in the brain.

Impulses from the brain and spinal cord join the autonomic network of nerves along nerve fibres which run into ganglia (rather like electrical switch-boxes). The impulses are transmitted at these junctions by chemical transmitters (nerve transmitters). The nerve fibres running to the junctions are called pre-ganglionic nerve fibres and they all use the same chemical transmitter – acetylcholine. This only works for a very short time because once it is liberated at nerve junctions to act as a nerve transmitter another chemical starts to break it down. This chemical is an enzyme called cholinesterase. Nerve fibres running from the nerve junctions (ganglia) are called post-ganglionic nerves.

Parasympathetic post-ganglionic nerves also use acetylcholine as a nerve transmitter – they are therefore known as cholinergic nerves, but the sympathetic post-ganglionic nerve fibres use adrenaline(epinephrine) and noradrenaline(norepinephrine) as chemical transmitters and therefore these are known as adrenergic nerves. The central part (medulla) of the adrenal glands also produces adrenaline(epinephrine) and noradrenaline(norepinephrine).

Drugs which Act on the Parasympathetic Nervous System

Drugs which act like acetylcholine were called cholinergic drugs – they are now called parasympathomimetic because they mimic the actions of the parasympathetic nervous system.

Stimulation of the parasympathetic division produces stimulation of secretory glands – salivary, tear, bronchial and sweat. It slows the heart rate, constricts the bronchi, produces increased movement of the intestine, contracts the bladder and constricts the pupil. Parasympathomimetic drugs also stimulate nerve endings in voluntary muscles, stimulate and then depress the brain, and dilate blood vessels.

Parasympathomimetic Drugs

Parasympathomimetic drugs mimic the actions of acetylcholine. There are three groups:

(1) Choline esters (e.g. carbachol, bethanechol) – these are related to acetylcholine and act at all sites like acetylcholine.

(2) Alkaloids (e.g. pilocarpine) – these are obtained from plants and act selectively on those nerve endings which respond to acetylcholine.

(3) Cholinesterase inhibitors or anticholinesterase drugs (e.g. pyridostigmine, neostigmine) – these inactivate the enzyme (cholinesterase) which is responsible for breaking down acetylcholine into acetic acid and choline, and therby inactivating it. This allows acetylcholine to go on working. Cholinesterase inhibitors are also used in the treatment of Alzheimer’s disease due to evidence which shows that they can enhance cognitive function. They include donepezil (Aricept), galantamine (Reminyl) and rivastigmine (Exelon).

Parasympathomimetic drugs produce similar effects to stimulating the parasympathetic division. But not all   effects occur with each drug and also the intensity of effects varies. Acetylcholine is not usually used in drug treatments. Carbachol (Isopto Carbachol) and Pilocarpine (Isopto Carpine, Ocusert, Pilogel, Salagen) are used to constrict the pupil and decrease the pressure inside the eye in patients with glaucoma. Carbachol may also be used to stimulate bowel and bladder function after surgical operations. It may be given by injection under the skin or by mouth. Bethanechol (Myotonine) is related and may be given by mouth to treat acid reflux (reflux oesophagitis) and retention of urine.

The anti-cholinesterase drug neostigmine (Robinul) may be used to stimulate the bowel and bladder after surgery. Endrophonium is used to diagnose, and neostigmine (Robinul) and pyridostigmine (Mestinon) are used in the treatment of myaesthenia gravis (a disease caused by defective transmission of impulses by acetylcholine and characterized by severe muscle weakness and fatigue). They are used as antidotes to neuromuscular blocking drugs (p. 39).  Pyridostigmine (Mestinon) is also used to treat paralysis of the bowel (paralytic ileus). Distigmine (Ubretid) is longer-acting than pyridostigmine and is used to stimulate the bowels after surgery, to treat myasthenia gravis and to treat incontinence of the bladder. Many related drugs are also ‘used’ as nerve gases and some are pesticides.

Drugs which Oppose Acetylcholine Activity

These may be called acetylcholine antagonists or parasympatholytics. They prevent acetylcholine from acting as a transmitter.

One of the main classes of anticholinergics are referred to as antimuscarinics because they block the actions of acetylcholine at muscarinic receptors. This is a more accurate term for the anticholinergics used as medicines. The other main group of anticholinergics work on nicotine receptors. In medicine they are used as ganglion blockers and skeletal muscle relaxants.

There are three groups:

(1) Antimuscarinic drugs which act principally at parasympathetic nerve endings.

(2) Ganglion blocking drugs which act on ganglia (and don’t forget that acetylcholine is the chemical transmitter in all ganglia – both in the parasympathetic and sympathetic divisions).

(3) Neuromuscular blocking drugs – these act on nerve endings in voluntary muscles.

(1) Antimuscarinic drugs. Antimuscarinic drugs block the action of acetylcholine on acetylcholine receptors in the tissues and organs of the body. In addition, some of them have a weak effect in blocking acetylcholine in the main switchboxes (ganglia) of the autonomic nervous system (affecting both

sympathetic and parasympathetic divisions). No antimuscarinic drug blocks the action of acetylcholine at nerve endings in voluntary muscles, except propantheline in very high doses.

There are several groups of antimuscarinic drugs which produce differing degrees of effects in the body. For example, some produce more effects on the brain and/or the eyes than the others, some produce more effects on the stomach or intestine, and some are much more selective in their actions than others.

Antimuscarinic drugs obtained from plants include atropine, belladonna, hyoscine and hyoscyamine. They produce similar effects and their uses are listed later.

Synthetic antimuscarinic drugs may be divided into three groups according to whether their principal actions are in drying up secretions and reducing movements of the intestines (anti-secretory and anti-spasmodic); whether they reduce the shaking and excessive salivation in patients with parkinsonism (anti-parkinsonism effects); or whether their main effects are upon the eyes (mydriatic and cyclopegic effects).

Those used mainly for their anti-secretory/anti-spasmodic effects include dicycloverine(dicyclomine) (Merbentyl, in Kolanticin), glycopyrronium (Robinul), poldine and propantheline (Pro-Banthine).

Those used mainly to treat parkinsonism include trihexyphenidyl(benzhexol) (Broflex), benztropine (Cogentin), biperiden (Akineton), orphenadrine (Biorphen, Disipal) and procyclidine (Arpicolin, Kemadrin).

Those used mainly to treat eye disorders include cyclopentolate (Mydrilate) and tropicamide (Mydriacyl).

The principal uses of antimuscarinic drugs therefore include the treatment of parkinsonism and motion sickness, as sedatives, to dilate the pupils, to dilate the bronchi and reduce bronchial secretions, to reduce acid production by the stomach in the treatment of peptic ulcers, to treat colic, to reduce sweating and occasionally to treat heart block and slow pulse rates.

(2) Ganglion blocking drugs. These have been used in the past to treat raised blood pressure. They lower blood pressure by producing dilatation of blood vessels and therefore a fall in peripheral resistance. They included hexamethonium, mecamylamine, pempidine and pentolinium. Because they are not selective and block ganglia in both parasympathetic and sympathetic divisions, they produce numerous adverse effects. Trimetaphan is used to keep the blood pressure low during surgery.

(3) Neuromuscular blocking drugs (myoneural blocking drugs). When an impulse passes down a nerve to a voluntary muscle it causes the release of acetylcholine at the nerve ending which acts as a chemical transmitter stimulating the muscle to contract. Neuromuscular blocking drugs interfere with this chemical transmission. Curare, used on poisoned arrows by the natives of South America, is the most famous example of this group of drugs. There are two main ways in which neuromuscular blocking drugs work. Atracurium (Tracrium), cisatracurium (Nimbex), gallamine (Flaxedil), mivacurium (Miracrin), pancuronium (Pavulon), rocuronium (Esmeron) and vecuronium (Norcuron) compete with acetylcholine and block the impulse being transmitted to the receptor organ in the muscles. They cause a prolonged paralysis of voluntary muscles. They are referred to as competitive neuromuscular blocking drugs (or non-depolarizing muscle relaxants) and are used to relax muscles during surgery and in long-term mechanical ventilation. Drugs such as suxamethonium (Anectine) mimic the action of acetylcholine – at first they cause the muscles to contract but this effect wears off quickly and they leave the muscle no longer receptive to stimulation by acetylcholine. They are referred to as depolarizing neuromuscular blocking drugs because they block the complex physicochemical process called polarization. Suxamethonium produces its effects for only a few minutes and it is used to provide muscle relaxation for procedures such as passing a tube into the lungs.

Drugs which Act on the Sympathetic Nervous System

Those drugs that imitate the effects of stimulation of the sympathetic division are called sympathomimetic drugs. Those that oppose its effects are called sympatholytic.

Sympathomimetic Drugs

This group of drugs includes adrenaline(epinephrine) and noradrenaline(norepinephrine), which are secreted by the medulla of the adrenal glands. Noradrenaline(norepinephrine) is also the main chemical transmitter at post-ganglionic sympathetic nerve endings. These nerves are therefore called adrenergic nerves and drugs which stimulate them are called adrenergic drugs – those that oppose their action are called adrenolytic.

Noradrenaline(norepinephrine) is produced and stored at adrenergic nerve endings and can be liberated from these stores by stimulating the nerve, or by drugs such as amphetamines, ephedrine, reserpine and guanethidine. Sympathomimetic drugs (or adrenergic drugs) may act directly on the receptors at the nerve endings of the sympathetic nervous system (e.g. adrenaline(epinephrine), noradrenaline(norepinephrine), isoprenaline (Saventrine)); indirectly by stimulating the liberation of noradrenaline(norepinephrine) from the stores at the nerve endings (e.g. amphetamines); or by both indirect and direct actions (e.g. ephedrine, metaraminol (Aramine)).

Sympathomimetic drugs act on adrenergic receptor sites which are found widely distributed throughout the body. These receptors are classified simply into alpha (a) and beta (b1 and b2) receptors. Stimulation of alpha receptors produces what are called alpha effects – constriction of arteries in the skin and intestine, sweating and dilatation of the pupils. b1 receptors are principally located in the heart; stimulation produces an increase of heart rate and increased output of blood from the heart. Stimulation of b2 receptors

produces relaxation of bronchial muscles, relaxation of the uterus, dilatation of arteries (chiefly in muscles), and tremor of skeletal muscles.

Adrenaline(epinephrine) produces both alpha and beta effects, noradrenaline(norepinephrine) produces chiefly alpha effects and isoprenaline produces beta effects.

Sympathomimetic drugs are principally used:

as nasal decongestants: read chapter 10 on drugs used to treat the common cold.

to treat bronchospasm: read chapter 14 on drugs used to treat bronchial asthma.

to treat low blood pressure: those sympathomimetics that constrict arteries are occasionally used to raise the blood pressure in severe states of low blood pressure caused by coronary thrombosis, anaesthetics or drug overdose. They include ephedrine, metaraminol, methoxamine, noradrenaline(norepinephrine) and phenylephrine.

to treat premature labour: ritodrine (Yutopar), salbutamol and terbutaline cause relaxation of the womb and are used to stop premature labour.

to treat heart failure (see p. 107).

Drugs which Oppose Sympathetic Activity

These drugs oppose sympathetic activity:

(1) Adrenergic neurone blocking drugs. These block transmission of nerve impulses along post-ganglionic sympathetic nerves (adrenergic nerves) or their nerve endings. They include debrisoquine and guanethidine (Ismelin). These drugs are discussed in chapter 25 - drugs used to treat raised blood pressure.

(2) Alpha-adrenoreceptor blocking drugs. These include alfuzosin (Xatral), doxazocin (Cardura), indoramin (Doralese, Baratol), phentolamine (Rogitine), phenoxybenzamine (Dibenyline), prazosin (Hypovase) and terazosin (Hytrin). The principal effect of these drugs is to produce dilation of arteries. They are also discussed in Chapter 25. They are also used (except for phentolamine and phenoxybenzamine) to improve the flow of urine in men with enlarged prostate glands (see page 251).

(3) Beta-receptor blocking drugs. These are used to treat angina, disorders of heart rhythm, raised blood pressure, over-active thyroids, anxiety and migraine. 

Summary: Drugs which Act on the Autonomic Nervous System  

Parasympathetic Division

Parasympathomimetic drugs

•           choline esters (e.g. carbachol)

Cholinergic drugs •                                 alkaloids (e.g. pilocarpine)

•           cholinersterase inhibitors (e.g. neostigmine)

Parasympatholytic drugs

Anticholinergic drugs, e.g. atropine

Ganglion blocking drugs (block ganglia in both parasympathetic and sympathetic divisions), e.g. mecamylamine

Sympathetic Division

Sympathomimetic drugs

•           alpha-receptor stimulants (e.g. noradrenaline(norepinephrine))

Adrenergic drugs •                  alpha-and beta-receptor stimulants (e.g. adrenaline(epinephrine))

  •           beta-receptor stimulants (e.g. isoprenaline)

Sympatholytic drugs

Adrenergic neurone blocking drugs, e.g. guanethidine

Alpha-receptor blocking drugs, e.g. phentolamine

Beta-receptor blocking drugs, e.g. propranolol

Alpha and beta blocking drugs, e.g. labetolol

Other Nerve Transmitters

Dopamine

Dopamine stimulates dopamine receptors in the brain and nervous system and also alpha and beta adrenoreceptors. It can also stimulate the release of noradrenaline(norepinephrine) from nerve endings. It is used to stimulate the heart in acute heart failure and in heart surgery.

Dopamine-stimulants

Amantadine (Symmetrel) is used to treat parkinsonism (see Chapter 16). It stimulates an increase in concentration of dopamine in the brain.

Bromocriptine (Parlodel) is a selective dopamine receptor stimulant. It is used to suppress milk production after childbirth because it blocks the release of the milk-producing hormone prolactin by the pituitary gland, and to treat tumours which produce excessive amounts of prolactin. It also blocks the release of growth hormone by the pituitary gland and may be used to treat overproduction of this hormone (e.g. acromegaly). Another main use of bromocriptine is to treat parkinsonism (see Chapter 16).

Levodopa is a precursor of dopamine and is used to treat parkinsonism (see Chapter 16).

Lisuride and Pergolide (Celance) are selective dopamine receptor stimulants used to treat parkinsonism (see Chapter 16).

Selegiline (Eldepryl, Zelapar) is a selective blocker of the enzyme that breaks down dopamine and is used to treat parkinsonism (see Chapter 16).

Dopamine-blockers

Certain anti-psychotic drugs (e.g. phenothiazines) used to treat serious mental disorders block dopamine receptors. They may produce adverse effects similar to parkinsonism which is caused by a deficiency of dopamine in the brain (see Chapter 16). They are also used to treat nausea and vomiting (see Chapter 18).

Other dopamine blockers (e.g. domperidone (Motilium) and metoclopramide (Maxolon, Gastrobid, Gastroflux, Primperan)) are also used to treat nausea and vomiting (see Chapter 18).

Tetrabenazine reduces the concentration of dopamine in the brain and nervous system and is used to treat disorders of movement such as Huntington’s chorea.

5-Hydroxytryptamine (5HT, serotonin)

This chemical is present in many cells in both plants and animals. It has a wide spectrum of activity by stimulating and blocking nerves in smooth muscles (particularly in the breathing tubes, producing wheezing), and in blood vessels; it also produces constriction in some muscles. It produces a slowing of the heart rate, a fall in blood pressure and affects the movements of the stomach and intestine. It also acts as a nerve transmitter in the brain and affects mood and behaviour.

Most of the 5HT in food is destroyed in the walls of the intestine and, if it is absorbed, in the liver and the lungs. Therefore, it is manufactured in the body from tryptophan (an essential amino acid in the diet).

5HT stimulants

Drugs that increase the amount of 5HT (serotonin) available in the brain are used to treat depression. They are discussed in Chapter 4. (See p.18).

5HT Blockers

Methysergide (Deseril) blocks 5HT at its receptor sites and is used to prevent migraine (see Chapter 34).

Pizotifen (Sanomigran) is a 5HT blocker that is also used to prevent migraine.

Antipsychotic drugs block the activity of dopamine in the brain and they may also block the activity of 5HT.

Cyproheptadine (Periactin) is an antihistamine that also blocks the effects of 5HT. It is used to treat migraine.

Granisetron (Kytril), ondansetron (Zofran) and tropisetron (Navoban) are selective 5HT blockers used to treat nausea and vomiting caused by anti-cancer drugs and radiation treatment. See Chapter 18.

Drugs which Enhance Neuromuscular Transmission

In conditions such as myasthenia gravis, anticholinesterase drugs are used. They prolong the action of acetylcholine by inhibiting the action of the enzyme acetylcholinesterase which breaks down acetylcholine. They may produce adverse effects such as increased sweating, salivation, and gastric secretion, increased contractions in the gut and uterus, and slowing of the heart rate. These drugs include distigmine (Ubretid), edrophonium, neostigmine and pyridostigmine (Mestinon). They vary according to their duration of action. Their effects can be stopped by giving atropine.

Muscle Relaxants Used in Anaesthesia

Drugs which block the transmission of nervous impulses at neuromuscular junctions are used in anaesthesia. They are usually referred to as neuromuscular blocking drugs or myoneural blocking drugs. They make muscles relax during surgery (e.g. abdominal muscles) and they make the vocal cords relax so that a tube can be passed down into the lungs in order to give anaesthetic gases. As stated earlier, there are two groups of neuromuscular blocking drugs. The first are those that compete with acetylcholine and block its effects (non-depolarizing muscle relaxants). They include atracurium (Tracrium), cisatracurium (Nimbex), gallamine (Flaxedil), mivacurium (Mivacron), pancuronium (Pavulon), rocuronium (Esmeron), vecuronium (Norcuron). The second group are depolarizing muscle relaxants which mimic the action of acetylcholine and cause blockage of impulses at neuromuscular junctions. Suxamethonium (Anectine) is the most commonly used.

Skeletal Muscle Relaxants

Muscle relaxants used to relieve pain and spasm in skeletal muscles act principally on the brain and spinal cord. Drugs used include benzodiazepines e.g. diazepam (see p. 9) and baclofen (Baclospas, Balgifen, Lioresal). Dantrolene (Dantrium) acts directly on skeletal muscles to produce relaxation but produces adverse effects on the brain. Quinine is useful for relieving leg cramps in bed at night. Other muscle relaxants include carisoprodol (Carisoma) and methocarbamol (Robaxin). Tizanidine (Zonaflex) is an alpha2-adrenoceptor agonist indicated for spasticity associated with multiple sclerosis or spinal cord injury.

 

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