Ординатура / Офтальмология / Английские материалы / Ophthalmic Drugs Diagnostic and Therapeutic Uses 5th edition_Hopkins, Pearson_2007

GENERAL PHARMACOLOGICAL PRINCIPLES 27

Reversible The best known example of these compounds is physostigmine from the anticholinesterases calabar bean. Neostigmine is a more modern synthetic copy which has

the advantage of greater stability.

Irreversible Originally developed as nerve gases and insecticides, the organophos- anticholinesterases phorous compounds produce an inhibition of cholinesterase that is so

prolonged that it is thought that the body produces new enzyme before the original has been regenerated. One of the original compounds was diisopropylfluorophosphate (DFP), which has been superseded by more stable compounds

The effects of anticholinesterases are similar to those of parasympathomimetics, with additional effects due to the nicotinic actions of causing enhanced transmission, which is sometimes evident as muscle fasciculation or twitching. Anticholinesterases, in addition to their ophthalmic application, are used in the treatment of myasthenia gravis.

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across the neural muscular junction. They produce their effect by one of two methods: (1) competitive blockade or (2) depolarizing blockade. In the former, the motor endplate is maintained in its polarized, unstimulated resting state by the blocking drug, which occupies the receptor without producing the action potential necessary for muscle contraction. Drugs like tubocurarine work in this manner and, as they are competitive agents, will be reversed by increasing the amount of normal transmitter at the motor endplate. Thus their effects can be reversed to some extent by the use of an anticholinesterase.

Depolarizing blocking drugs maintain the motor endplate in a depolarized state and prevent repolarization, which is necessary for the initiation of a new AP. For normal skeletal muscle this results in a relaxation but certain muscle fibres, such as those found in the oculorotatory muscle, respond by going into a sustained contraction – contracture. The administration of an anticholinesterase will result in a deepening of blockade.

ADRENERGIC RECEPTORS

Noradrenaline, adrenaline and other catecholamines that act as neurohumoral transmitters (e.g. dopamine) can cause either excitation or inhibition of smooth muscles, depending on the site and amount of catecholamine present. Catecholamines are a group of chemical compounds (catechol is dihydroxybenzene) distributed throughout the tissue of the body in cells called chromaffin cells, due to the brown colour of the latter produced when they are treated with dichromate. The actual percentage of these catecholamines in various tissues depends on the site in the body. For example, the adrenal medulla secretes 80% adrenaline, the remainder of its secretion being noradrenaline, very little dopamine being present. The transmitter liberated from adrenergic nerve fibres is noradrenaline, with perhaps a little adrenaline. The most potent excitatory catecholamine is noradrenaline, which has a correspondingly low activity as an inhibitor; adrenaline is relatively potent in both excitatory and inhibitory activities.

Ahlquist (1948) studied the excitatory and inhibitory actions of various catecholamines [including L-adrenaline, DL-adrenaline, noradrenaline, methyl-noradrenaline, methyl-adrenaline and isopropyl noradrenaline (isoprenaline)] using vascular, bronchial, stomach, intestinal, uterine and ureter smooth muscle, cardiac muscle and the smooth muscle in the nictitating membrane of the cat. He proposed the terms ‘alpha-receptor’ and ‘beta-receptor’ for adrenoreceptive sites on smooth muscles where catecholamines produce excitation or inhibition, respectively. Both types of receptor can be present in the same tissue. This occurs in blood vessels, where with the usual amounts of physiologically circulating adrenaline, the beta-receptor response (vasodilatation) predominates in the blood vessels of the skeletal muscle and the liver whereas the alpha-receptor response (vasoconstriction) occurs in blood vessels of the abdominal viscera, skin and mucosa (including the conjunctival vessels).

GENERAL PHARMACOLOGICAL PRINCIPLES 29

Exceptions to the general proposal associating alpha-receptors with excitation and beta-receptors with inhibition are recognized. An inhibitory response is mediated by both alphaand beta-receptors in the intestine, the latter being generally relaxed by catecholamines. Developments in the study of adrenergic receptors have led to the division of alpha receptors into alpha-1 and alpha-2, based on their molecule mode of action.

On the basis of relative selectivity of effects of both excitatory and antagonist agents, Lands et al (1967) demonstrated two different types of beta receptor. Excitatory responses and positive chronotropic and inotropic effects (increased rate and force, respectively) are the response of cardiac nodes and muscle that contain beta-receptors. In the heart, these have been classified as beta-1 receptors. Most of the other betareceptors that produce inhibition are known as ‘beta-2 receptors’. There is now a beta-3 receptor, which is found in fat cells and brings about lipolysis in the intestine.

Whichever beta receptor is involved, the basis of action is the activation of a membrane enzyme. This leads to the conversion of adenosine triphosphate into cyclic adenosine monophosphate cAMP, which leads to a series of complex events culminating in the pharmacological response.

Drugs acting on the sympathetic nervous system can produce their effect by a variety of mechanisms:

•direct-acting sympathomimetics

•indirect-acting sympathomimetics

•drugs that interfere with the neuronal reuptake of noradrenaline

•adrenergic receptor-blocking drugs

•adrenergic neuron-blocking drugs.

Direct-acting These drugs are directly comparable with parasympathomimetics in that sympathomimetics they mimic the effect of natural transmitter on the adrenergic receptor, which is normally but not exclusively found opposite nerve terminals.

Because their action is direct they do not need the presence of the nerve terminal. As the basis of the classification of the adrenergic receptor is the differential effects of the various sympathomimetics, it follows logically that some drugs will predominantly affect alpha-receptors (e.g. noradrenaline) whereas others (e.g. isoprenaline) will predominantly affect beta-receptors. The two groups are not mutually exclusive and noradrenaline will stimulate the heart and produce bronchial dilation whereas isoprenaline will constrict blood vessels and cause a rise in blood pressure. Their effect is enhanced by sympathetic denervation.

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DENERVATION SUPERSENSITIVITY

When the nerve to an effector cell is cut or destroyed, the cell becomes supersensitive to the transmitter normally supplied by the nerve or to any drug capable of mimicking its effects. This supersensitivity is brought about by the lack of a neurotropic factor that is present when the nerve is functioning.

GENERAL PHARMACOLOGICAL PRINCIPLES 31

The mechanism of supersensitivity is due to an increased number of receptors and an absence of the reuptake mechanism in the case of sympathetic nerves. It can be produced chemically using 6-hydroxydopamine or pharmacologically with guanethidine, as well as surgically. It also occurs spontaneously in Horner’s and Adie’s syndromes, in which the sympathetic and parasympathetic nervous systems, respectively, are affected. When the nerve returns to normal (regenerates), the effector cell loses its supersensitivity.

References

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Chapter 2

Ocular autonomic innervation

EFFECTOR STRUCTURES IN THE EYE AND ORBIT

Many of the diagnostic drugs used in ophthalmic practice, in particular cycloplegics, mydriatics and miotics, directly or indirectly produce their effects by stimulating or inhibiting that part of the autonomic nervous system (ANS) that supplies the intraocular muscles. They might, in addition, have an effect on other smooth muscles or glands in the orbit. It is therefore essential, before proceeding to a more detailed discussion on the actions and uses of ophthalmic autonomic drugs, to have a basic understanding of the structure and function of this involuntary nervous system in the orbital region.

INTRAOCULAR MUSCLES

Ciliary muscle This muscle consists of flat bundles of unstriped fibres, which can be classified as follows (Fig. 2.1):

•meridional fibres (Brücke’s muscle)

•radial fibres

•circular fibres (Müller’s muscle).

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PARASYMPATHETIC INNERVATION OF THE EYE

The ciliary muscle is innervated by parasympathetic cholinergic fibres running in the third cranial nerve (the oculomotor); their origin is in the Edinger–Westphal nucleus near the third nucleus in the floor of the aqueduct of Sylvius (Fig. 2.2). From here, they pass out of the midbrain in the main trunk of the third nerve, which, just before entering the orbit, divides into superior and inferior divisions. The parasympathetic fibres continue in the inferior division and pass into its inferior oblique branch, which they leave to form the motor root of the ciliary ganglion. In this ganglion the parasympathetic fibres synapse, their postganglionic components, which are atypical in being medullated, entering the globe via the short ciliary nerves (6–10), which pierce the sclera around the optic nerve. The parasympathetic fibres then pass forward in the perichoroidal space to supply the ciliary and sphincter pupillae muscles. The Edinger–Westphal nucleus, according to Miller (1978), receives excitatory connections from the frontal and occipital (psycho-optical) cortex.

The parasympathetic (secretomotor) fibres to the lacrimal gland have their origin in cells forming a discrete subnucleus located very close to the superior salivatory nucleus, which lies lateral to the nucleus of the

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seventh cranial nerve beneath the floor of the pontine part of the fourth ventricle. Leaving the brain stem in the nervus intermedius, between the pons and inferior cerebellar peduncle, they run with the seventh nerve, fusing with the latter at the geniculate ganglion.

From this ganglion arises the great (superficial) petrosal in which the parasympathetic fibres run to join the deep petrosal (sympathetic) to form the nerve of the pterygoid canal (the Vidian). This nerve joins the pterygopalatine (sphenopalatine, or Meckel’s) ganglion, where only the parasympathetic component relays, the postganglionic parasympathetic fibres then travel via the maxillary nerve to enter its zygomatic branch and reach the lacrimal gland via a connecting branch of this nerve.

SYMPATHETIC INNERVATION OF THE EYE AND ORBIT

The preganglionic sympathetic nerve fibres of the dilatator tract supplying the dilatator pupillae muscle probably have their origin in the hypothalamus, not far from the constrictor centre (Edinger–Westphal) to which they are connected by, Miller (1978) considers, an inhibitory pathway, in addition to having connections with the cerebral cortex (see Fig. 2.2). The dilatator nerve fibres pass downwards, with partial decussation in the midbrain, through the medulla oblongata into the lateral columns of the cord. They leave the latter by the anterior roots of the first three thoracic nerves and perhaps the last cervical nerve, passing to the corresponding lateral ganglion chain on each side via the white rami communicantes. These sympathetic nerve fibres then run to the first thoracic (or stellate) ganglion, as the frequently found fused first thoracic and inferior cervical ganglion is termed, and from there into the cervical sympathetic chain in the neck, synapsing in the superior cervical ganglion, which is the peripheral ganglion in their path from the central nervous system to the orbit. The non-medullated postganglionic fibres enter the cranial cavity in company with the internal carotid artery around which they form networks, the carotid plexus, and a little further on, where this artery lies within the cavernous sinus, the cavernous plexus. It is mainly from the latter that most of the sympathetic nerves to the eye and orbit are derived. The dilatator fibres pass from the cavernous plexus to run over the anterior part of the trigeminal (or Gasserian) ganglion before entering the ophthalmic division of the fifth cranial nerve, the sympathetic fibres continuing in its nasociIiary branch. They leave this nerve to enter the long ciliary nerves, which enter the eye on either side of the optic nerve. Running forward in the perichoroidal space, the sympathetic fibres then pass through the ciliary body to reach the dilatator pupillae in the iris.

Other postganglionic sympathetic fibres from the cavernous plexus form the sympathetic root of the ciliary ganglion, passing through it, without further synapse, to enter the eye via the short ciliary nerves to supply the intraocular blood vessels of the uvea. Also from the