|Year : 1982 | Volume
| Issue : 4 | Page : 191-194
Kinetics of drug distribution in ocular fluids
Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
V S Mathur
Associate Professor of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh-160-012
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Mathur V S. Kinetics of drug distribution in ocular fluids. Indian J Ophthalmol 1982;30:191-4
Anaesthetic agents, autonomic drugs, steroids, antibiotics and several other groups of drugs are used in ophthalmic practice today. These are usually administered locally and at times systemically. In order to produce its effect the drug must interact with the receptors. This can only happen when the drug reaches the site of action in at least the minimum effective concentration.
Advances in the quantitative aspects of biopharmaceutics have come about by the development of a new discipline. Pharmacokinetics. This branch of pharmacology deals with the study of the time course of absorption, distribution, metabolism and excretion of drug in the intact total organism. Kinetic models have been established to quantify and predict these dosage regiments.
What the drug does to the body is known as pharmacodynamics' and what the body does to the drug is known as 'pharmacokinetics'.
According to Gibald; "the purpose of pharmacokinetics is to study the time course of drug metabolite concentrations and amounts in various body fluids, tissues, excreta and thereby develop suitable mathematical models to describe and interpret absorption, distribution, metabolism and excretion process".
As has been mentioned earlier the drugs used in ophthalmic practice are administered
Locally-(a) Corneal application (b) Periocular injections (subconjunctival, retrobulbar and subtenon) (c) Intravitreal injection.
Systemically-Intramuscular or intravenous route, even orally
| Local administration|| |
Drugs may be applied to the eye in the form of sterile aqueous solutions, aqueous suspensions, ointments or inserts intended to reside in the conjuntival cul-de-sac. After application the drug has to penetrate the cornea-a barrier with both hydrophilic and lipophilic characteristics, before it gets into the aqueous humour bathing the lens. Penetration to the vitreous humour occurs through the perilimbal plexus, ciliary body and the iris. This quantity reaching vitreous by this route is very inadequate,
By the corneal route the drug would traverse to the various parts of the eye. The tissue concentration of a drug represents a balance between the rate of entrance of the drug across the appropriate site and its rate of removal. This depends upon aqueous flow, blood flow, destruction by the tissue and other factors. The penetration, however is another matter over which a certain degree of control can be exercised. This route is useful for structures located in the anterior segment of the eye only.
| Factors determining penetration|| |
1. Permeability of the barrier.
(a) Lipid solubility
(i) Steroids, chloramphenicol which are lipid soluble penetrate easily but not penicillin which is water soluble
(ii) Weak organic bases such as atropine and pilocarpine are lipid soluble and hence can get through easily in their undissociated form.
(iii) Wetting agents such as Benzalkonium increase the penetration of penicillin and streptomycin.
(b) Diffusion along fluid filled channels -by this mode water soluble molecules which are small enough get through.
2. Molecular weight : Larger the molecular weight of compound less likely it passes. Both chloramphenical and penicillin have this but as the former is lipid soluble it passes through.
3. Concentration gradient
(a) Drug concentration These factors influence the penetration,
(b) Duration of contact
4. pH : Within limits higher the pH better is the absroption e.g. Pilocarpine nitrate higher the pH the greater is the concentration of the free base.
5. Active transport : Penicillin is transported out of the eye via the ciliary epithelium. This transport mechanism tends to decrease the intra ocular levels of this antibiotic.
| Techniques employed in the study of topically applied drugs|| |
1. Drugs as drops over the eye and evaluation of its Physiologic response
2. Drugs as drops over the eye and at appropriate intervals measure their levels in aqueous humour.
3. Use of labelled compound and its estimation in the various components of the eye at different intervals after enucleation 1. Evaluation by physiologic response :- eg. changes of pupillary diameter after instillation of a miotic such as pilocarpine nitrate. In such a model both the effect of the concentration type of preparation and time of contact all can be studied.
In this connection it is to be remembered that the tear capacity in human beings is about 10µl and therefore one should have a volume around this to contain the drug. In case more than one drug has to be administered one should have concentrated solution containing the combinations in 10µI or so. When however two drugs are intended to be used a gap of about 4 nits. between drops must be given.
II. Evaluation by estimation of drug levels in aqueous humour. This is possible only in experimental animals and sometimes on human subjects during surgery.
In a study where flurometholone solution and suspension were studied it was observed that the suspension produced higher concentrations in the aqueous humour as the suspended porticles were retained in the cul-de sac. It was further observed that when 50 µl of 0.1% 0.05% and 0.01% suspension of the above steroid was instilled, the maximum concentrations were observed with the highest concentration i.e. 0.1%.
III. Estimation of labelled compound after eye removal at different time interval. Such a study is possible in experimental animals such as rabbits using a drug like tritrated pilocarpine Studies employing u.1 ml of a 2% solution of labelled pilocarpine in a number of rabbits which were sacrificed was carried out. The eyes removed aid kept in liquid nitrogen. The study revealed that the highest concentration occur in the aqueous humour, iris and ciliary body. The peak values were obtained in minutes. The penetration was better when the drug cornea was applied to rather than conjuntiva. This was done by putting up discs containing the drug in specific areas.
Periocular and Intravitreal injection : These modes of administration of drugs have recently been claimed to play an important role in the management of bacterial endophthalmitis and for conditions wnen adequate concentration, are required for tissues in the posterior segment.
In this connection I would like to refer the experimental studies mostly in rabbits which have shown higher concentrations of antibiotic: in choroid, retina and vitreous after perioculal injections than after I.V. or I.M. injections These studies could be more useful if these are repeated in primates.
It has demonstrated that when cefazolir was administered sub conjuntivally, ever with 1 / 10 the dose higher concentration irr ocular tissues were obtained. Antibiotic; administered either by the sub-cojuntival retrobulbar/subtenon routes, according tc Baum, have produced desirable concentration in the posterior segment of the eye.
A systematic apprcach to intravitreal administration of drug was made by Peyman who injected varying doses of antibiotics (501, -10 mg) in 0.1 ml into the vitreous of rabbits to study its toxicity. The drug was injected through the pars plana into the anterior part of vitreous. The studies were extended in primates also. With the fundus under direct observation aqueous paracentesis was performed before or during intravitreal injection. This prevented an increase in intraocular pressure. Animals were evaluated for 3 .sub 4 weeks. On some eyes electroretinography was performed. After sacrifice of the animal all eyes were enucleated and prepared for light microscopy. With the help of the above method a non-toxic dose of antibiotic was established. This dose was then injected into the vitreous of a number of animals which were sacrificed at varying periods ranging from 0-96 hours after the drug administration. The eyes were enucleated and immediately frozen by immersing in liquid nitrogen. The frozen vitreous and aqueous were separated from the surrounding structures and the antibiotic concentration were assayed.
The efficacy of such a therapy was also studied in experimental animals inoculated bacteria or fungi-producing endophthalmitia, who were then treated with intra vitreal injection. In such injections this mode of drug administration gave very encouraging results.
Peymen and Sanders have thus been able to give the dosage schedule for intravitreal injections of various antibiotics and the duration of the effective concentration in the vitreous. eg. gentamicin intravitreal dose 0.4 mg, duration 72-96 hours; carbenicillin 2.0 mg, duration 16-24 hours. They have also tried a combination of gentamicin and dexamethasone. Further they have, also advocated. the use of antibiotics as vitrectomy infusion fluid eg. chloramphenicol 10-20 μg/ml, tobramycin 10-20 μg/ml and gentamicin 8 μg/n -:1.
| Systemically administered drugs|| |
Systemically administered drugs have to cross the blood aqueous barrier before they can reach the ocular tissues. The system of semipermeable membrane separating the blood from ocular cavity comprises the blood aqueous barrier. This has the relatively impermeable Capillaries which are retinal, retinal and uveal and uveal.
The factors influencing the transfer are similar to those of the cornea viz. molecular size, lipid solubility etc. thus chloramphenicol crosses the barrier easily but not penicillin. The permeability of the barrier is increased by inflammation, irradiation and anoxia. Cortisone has no effect. Substances of very large molecular weight such as insulin, trypan blue and dextran are held back. Drugs like eserine, DFP, phospholine iodide increase the protein content of the aqueous humour.
For the systemically administered drug perhaps the best example is that of acetzolamide. This is a drug which is an ideal one from the pharmacokinetic point of view. The drug is completely absorbed from the GIT and is excreted unchanged, its protein bindings is known.
With this drug it would be correct to say that both the pharmacokinetic and pharmacodynamic event have been unified as a relationship between the total amount of acetazolamide in the human body, the degree of enzyme inhibition in the ciliary epithelium and the effect on aqueous humour formation can all be correlated.
Thus in conclusion it can be said that if pharmacokinetics is utilized in the clinical setting of ophthalmic practice-it would certainly promote safe and effective therapeutic management of patients.