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

8OPHTHALMIC DRUGS

Figure 1.2 Mode of action of a pro-drug.

Adrenaline (Active)

Dipivalylepinephrine

(Inactive)

Pivalic acid (Carrier)

These enzyme reactions themselves are subject to modification, which accounts for part of the variability of response of the patient not only to the drugs therapeutic but also to its unwanted side-effects and toxic effects. Enzyme activity is finite and although – at normal substrate levels – increasing substrate levels will increase activity, a saturation level can be reached. In addition, many drug interactions result from the effect of one drug on the deactivating enzyme of another. If the interacting drug enhances the effect of the enzyme then the target drug will have less effect and increased levels might be required. However, deactivation is sometimes inhibited and toxic levels can be achieved from doses that would be tolerated in the absence of the interacting drug.

EXCRETION

The principal route for excretion either of unchanged drugs or metabolites is via the kidneys. The processes by which foreign substances are removed (cleared) from the plasma are exactly the same for naturally occurring endogenous substances (i.e. glomulerular filtration, active tubular transport and passive tubular reabsorption). Many factors affect the efficiency of this route of excretion. Reduced kidney function is present in neonates, geriatric patients and patients suffering from kidney disease. For these patients, assessment must be made of their normal renal clearance and the dose adjusted appropriately. Plasma proteins do not pass across the glomerular membrane and thus drugs bound to them will not be filtered. Tubular reabsorption will depend on the lipid solubility of the drug or metabolite and by modifying the pH of urine by administering sodium bicarbonate to raise it or ammonium chloride to reduce it, the reabsorption can be reduced or enhanced depending on the substance’s pKa.

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ability to combine with the receptor) and efficacy (produces a response from the membrane). However, according to the rate theory, an agonist is a drug that combines and dissociates rapidly with the receptor.

Unlike an agonist, an antagonist, although it will still have affinity (if it did not it would not react with the receptor), has little or no efficacy. According to the rate theory, such a drug would have the ability to combine with the receptor as rapidly as an agonist but, having formed a complex with the receptor, it would then dissociate very slowly. Again there is a comparison with the inhibition of an enzyme by a false substrate. It would be a very unusual situation in which an antagonist was present at a receptor site in the complete absence of a corresponding agonist. The effectiveness of the antagonist will depend on the relative concentrations of the two agents, that is, the antagonism is competitive; the term ‘competitive antagonist’ is used to describe such drugs. The type of chemical bond formed in the drug–receptor complex will vary from weak, tenuous bonds in the case of agonists to stronger and, in some cases, permanent bonds. In the latter case, the antagonism or blockade will be irreversible and new receptor molecules must be formed.

As our knowledge of pharmacology increases, so too does the number of receptor types and subtypes. As well as the well-known receptors for acetylcholine (ACh), adrenaline, histamine and serotonin, we now have evidence of specific receptors for opiates, dopamine, adenosine, insulin and glucagons, to mention a few. Many of these receptors are further subdivided in to subtypes.

Cholinergic and adrenergic receptors will be further discussed with the autonomic nervous system.

CONCENTRATION–RESPONSE RELATIONSHIPS

Many of the concentrations of drugs used in eyedrops have been arrived at empirically and tend to be continued in use although, in many situations, a lower concentration would suffice and result in less opportunity for adverse effects. However, it is important to be aware of the relationships that exist between drug doses and the responses produced. Of course, biological variability has an effect and responses between different subjects to the same dose will occur.

In this context, the term ‘concentration’ refers to the amount of the drug that is present at the receptor site and is available to react with the receptor. Drugs do not act at a distance and chemical bonding of a tenuous nature must occur. This concentration will not be the same as the concentration of drug in an eyedrop administered to the conjunctival sac, as many pharmacokinetic factors will affect the final concentration. However, the concentration at the receptor is not easy to measure and the dose or concentration applied is used in calculations.

The term ‘response’ is a little more difficult to define and will depend on the type of drug and the desired effect. One can choose a continuously measurable response from an individual animal or tissue (e.g. the size of the pupil). With some drugs, for example analgesics, such a convenient

GENERAL PHARMACOLOGICAL PRINCIPLES 11

measure is not available and populations of subjects must be used, choosing a convenient endpoint such as noticeable relief of pain. Because of biological variability, a proportion of subjects will achieve the endpoint at a relatively low dose and, as the dose increases so will this proportion, until a maximum of 100% is achieved. If a plot were to be made of the proportion of subjects achieving the endpoint against dose, it would be seen that the relationship is not a linear one. To overcome this, a value known as the ED50 is used. This is the dose (or concentration) at which 50% of the subjects achieve the endpoint. This can be compared with other drugs, to gain some idea of relative potency, and with the drug’s own LD50 (lethal dose 50 – the dose at which 50% of the test animals are killed) to assess the drug’s safety margin.

Returning to graded responses, such as our example of the pupil diameter, as opposed to all-or-none responses, it is possible to plot a curve of response (in our example this would be in millimetres) against the logarithm of the dose applied (Fig. 1.3). Below a certain level (threshold) no effect will be seen. Between this level and the maximal effect the curve is sigmoid. After the maximum is reached there is no increase in effect with increased dose. The dose–response curve of one drug does not tell us a great deal but when the curves of several drugs are plotted together, comparisons can be made between them. A drug with a steep slope will quickly pass from threshold level to maximum and will be difficult to use because of the danger of passing quickly to an overdose situation. Different drugs can be compared for their efficacy and potency. These terms are sometimes used interchangeably but mean different things. Efficacy refers to the maximum response that can be achieved, a more efficacious drug producing a greater maximal effect. Potency refers to the dose of drug required to produce a given effect. Some drugs are more potent than others (i.e. require smaller doses) but have the same efficacy, probably due to better absorption. This might not confer an advantage because the drug with a greater therapeutic potency might also have a greater potency for side-effects (Fig. 1.4).

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THE PERIPHERAL AUTONOMIC NERVOUS SYSTEM

Many ophthalmic drugs produce their effect by modifying the actions of the peripheral autonomic nervous system in some way. The study of their mode of action requires a basic knowledge of the anatomy and physiology of the autonomic nervous system (ANS).

DIVISIONS AND DISTRIBUTION

The ANS is responsible for the control of smooth muscle, cardiac muscle and exocrine gland cells that are not normally under voluntary control. It is thus sometimes referred to as the involuntary nervous system. The major divisions of the autonomic nervous system are the parasympathetic nervous system and the sympathetic nervous system, and these have many anatomical and functional differences. However, they share one important difference from the somatic nerve fibres that supply skeletal muscle, in that they possess a synapse outside the central nervous system (CNS). A synapse is a break in the continuity of the nerve pathway and across this gap normal axonal transmission is impossible; instead, transmission takes place by chemical means. Synapses occur in the swellings on nerves called ganglia. The nerve that leaves the CNS and conducts impulses to the ganglion is referred to as the preganglionic nerve; the nerve that conducts impulses from the ganglion to the effector organ is called the postganglionic nerve fibre.

Parasympathetic preganglionic nerves leave the CNS by two outflows – cranial nerves and the sacral nerves. Paraympathetic fibres are found in the IIIrd (oculomotor), VIIth (facial), IXth (glossopharyngeal) and Xth (vagus) cranial nerves and the pelvic nerves. The parasympathetic nervous system supplies the viscera in the thoracic and abdominal cavities and the autonomic structures in the head (e.g. salivary glands, intraocular muscles and lacrimal glands). The preganglionic nerve fibres are very long, as the ganglia in which they synapse are very close to the organs that the postganglionic fibres innervate (the effector organs).

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Table 1.1 Effector organ responses to autonomic impulses*

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being relatively impermeable to sodium while allowing comparatively easy traverse for other ions. The reverse operates for potassium ions in the resting potential state, when they are approximately 30–50 times more concentrated in the axoplasm than the extracellular fluid, these concentration gradients being maintained by pump and active transport mechanisms, involving an adenosine triphosphatase (ATPase) at the inner surface of the membrane activated by sodium and at its outer surface by potassium (Thomas, 1972). The rapid inflow of sodium ions is immediately followed by increased membrane permeability for potassium ions, which flow in the opposite direction to the sodium ions. The local circuit currents around the axon, produced by these transmembrane ionic currents, activate adjacent regions of the axon, propagating the nerve AP along it, the recently activated region remaining momentarily in a refractory state. Very few drugs in normal therapeutic doses, with the exception of high concentrations of local anaesthetics infiltrated in the immediate vicinity of nerve trunks, modify axonal conduction.

JUNCTIONAL TRANSMISSION

Junctional transmission is the passage of an impulse across a synaptic or neuroeffector junction. The arrival at the axonal terminals of the AP initiates the neurohumoral transmission of an excitatory or inhibitory impulse. The following events occur (Fig. 1.5).

Release of transmitters Transmitters are largely synthesized in the region of the axonal terminals (some in the cell body) and stored there in synaptic vesicles, either in highly concentrated ionic form [as with acetylcholine (ACh)] or as a readily dissociable complex or salt [as with noradrenaline and adenosine triphosphate (ATP)] and a specific protein. Slow release of small amounts of these transmitters does take place in the resting state but this is insufficient to initiate a propagated impulse at the postjunctional site. The AP precipitates a simultaneous release of larger amounts of transmitter (several hundred quanta). This process is triggered by the depolarization of the axonal terminal. Although the other intermediate steps are uncertain, one step is the mobilization of the calcium ion, which enters the intra-axonal medium and is thought to promote fusion of the vesicular and axoplasmic membranes. The process by which the contents of the vesicle are then discharged to the exterior is termed ‘exocytosis’.