Textbook On Clinical Ocular Pharmacology & Therapeutics (079-117)

54 Textbook on Clinical Ocular Pharmacology and Therapeutics
Figure 4.6 Transmembrane signaling by tyrosine kinase linked receptors
5-diphosphate (PIP2), a phospholipid component causing membrane hyperpolarization and reduced

of plasma membrane. As a result of hydrolysis, neurotransmitter release.11
PIP2 splits into diacylglycerol (DAG) and inositol
3. Enzyme-linked receptors (Type III receptors):
1, 4, 5-triphosphate (IP3). IP3 diffuses out into
These transmembrane receptors have an
the cytoplasm and causes release of Ca2+ from
extracellular domain for binding with the ligand
intracellular storage sites. The released Ca 2+
(agonist) and an intracellular domain linked to an
binds to Ca2+ binding protein calmodulin, which
then regulates activity of various enzymes and enzyme such as tyrosine kinase. Agonist binding
produces responses like contraction and secretion. with the receptor causes conformational changes in
DAG activates Ca2+ sensitive protein kinase C, receptor leading to receptor autophosphorylation,
which in turn causes phosphorylation of proteins dimerization and activation of tyrosine kinase.
and brings about the cellular responses. Action Activated tyrosine kinase activates intracellular
of IP3 is terminated by its dephosphorylation signaling proteins leading to altered cellular
to phosphotidyl inositol monophosphate (PIP), functions (Fig. 4.6). Examples of this type of
a precursor of PIP 2 (Fig. 4.5). DAG is either receptors include insulin receptors, growth
converted back to phospholipids or gets acetylated hormone receptors. Nitric oxide receptors have
to arachidonic acid. Ca2+ returns back to storage guanylyl cyclase at their intracellular domain
sites by active transport. Examples of this type instead of tyrosine kinase. Receptor activation
of receptors include muscarinic receptors, α1 by ligand binding causes synthesis of a second
adrenergic receptors.10 messenger, cyclic GMP, that brings about cellular
responses.
Ion channel regulation: Some of the GPCR
regulate opening or closure of ion channels in 4. Cytoplasmic receptors (Type IV receptors):
response to interaction with agonists without The cytoplasmic receptors are precisely nuclear
intervening second messengers. For example: receptors. Interaction with ligand at their ligand
rhodopsin located in the disc membrane of binding domain unmasks their DNA-binding
the outer segment of rods is a GPCR. Upon domain. The unmasked DNA-binding domain now
activation by light, the covalently attached binds with the DNA of specific genes and activates
chromophore 11-cis retinal isomerizes to all- RNA polymerase. Activated RNA polymerase
trans retinal. Isomerization causes G-protein leads to synthesis of a specific m-RNA, which
activation and dissociation of α subunit and directs synthesis of specific proteins and produces
activation of phosphodiesterase that hydrolyzes cellular responses (Fig. 4.7). Examples of this type
cyclic GMP. Reduced cellular cyclic GMP causes of receptors include steroid hormone receptors,
closure of cGMP-sensitive sodium channels thyroid hormone receptors.
Pharmacodynamics 55
Figure 4.7 Regulation of DNA transcription by steroids through

intracellular receptors
Modified Receptor Actions number of receptors respond excessively to

endogenous catecholamines leading to rebound
Desensitization refers to reversible reduction hypertension. Therefore, in such cases the drugs
of receptor mediated response upon continued should be withdrawn by gradually tapering the
exposure to agonist. Continued exposure to dose with close clinical monitoring.
agonist causes conformational changes in receptor
Spare receptors refer to receptor reserve of
leading to tight binding with agonist without
the tissue. To achieve the peak effect it is not
producing the effect such as channel opening
necessary that all the receptors are occupied by the
at nicotinic neuromuscular junction receptors
drug molecules. Higher is the proportion of spare
or inability to activate adenylyl cyclase at
receptors for a drug in a tissue, higher is the tissue
adrenoreceptors.
sensitivity to that drug. For example: myocardium
Supersensitivity, upregulation and down- requires only 10% of its receptors to be occupied
regulation of receptors refer to increased or by catecholamines for peak effect and accordingly
decreased receptor sensitivity/expression on even if 80–90% of the catecholamine receptors
prolonged exposure to antagonist or agonist, are blocked, peak effect to catecholamines can
respectively. Continued exposure to antagonist still be elicited. This indicates high sensitivity of
causes increased number of receptors due to myocardium to catecholamines.
externalization of more receptors (upregulation).
Moreover, the sensitivity of receptors to available
agonists increases (supersensitivity). On the NON-RECEPTOR MEDIATED
other hand, continued exposure to agonist causes MECHANISMS OF DRUG ACTION
receptor internalization leading to decreased
Drugs may act by mechanisms other than receptor
number of receptors and decreased sensitivity.
mediated. Some of the non-receptor mediated
Prolonged treatment of bronchial asthma with
mechanisms of drug action are as follows:
β2 agonist causes reduction in response over
a period of time. This is because of receptor Chemical Reactions: Drugs may react chemically
downregulation. Receptor upregulation may be with endogenous substances to bring about
responsible for excessive rebound agonist action changes in physiological functions. For example:
after sudden withdrawal of a drug following long- antacids react with hydrochloric acid in stomach
term exposure leading to serious consequences. to neutralize it and, thereby reduce hyperacidity,
For example prolonged treatment of hypertension deferoxamine chelates with iron and facilitates
with non-selective β-blockers causes receptor excretion of excessive iron stored following
upregulation as well as supersensitivity. If the repeated blood transfusions, cholestyramine lowers
β-blockers are suddenly withdrawn, increased cholesterol level by exchanging with chloride ions
in bile salts and increasing its excretion. Inducing Antibody Formation: Vaccines, either
Physical Actions: Drugs may cause changes in by inducing antibody formation or by providing
physiological functions by virtue of their physical passive immunity, are effective in the prevention
properties. Mannitol reduces intraocular pressure and treatment of diseases. For example: smallpox
by drawing water out of intraocular tissue due vaccine, diphtheria antitoxin.
to its hyperosmolarity. Saline purgatives exert
high osmotic pressure in the lumen of gut. MEASUREMENT OF DRUG EFFECTS
Demulcents like pectin provide a protective
covering to inflamed mucosa and have soothing 1. Graded dose-response curve : The responses
effect. Astringents like tannic acid denature and following drug administration require
precipitate mucosal proteins and, thereby protect quantitative assessment in order to evaluate
mucosa by firming it up. Adsorbants like kaolin its safety and efficacy. Quantitative assessment
adsorb bacterial toxins and are useful as anti- of the magnitude of response as a function
diarrheal agents. of dose can be done using graded dose-
Targeting Enzymes: Some drugs act by response curve. It provides assessment of the
inhibiting the enzyme action, thereby altering relationship of the different doses (graded
the endogenous chemical reactions. For example: dose) with the corresponding responses in a
allopurinol, inhibits the enzyme xanthine oxidase, single individual/animal/isolated tissue. The
thereby reduces the synthesis of uric acid and is horizontal axis represents the dose while the
effective in the treatment of gout. Physostigmine vertical axis represents the response. The dose
inhibits acetylcholinesterase at neuromuscular on the horizontal axis is commonly plotted
junctions, thereby increases the availability of in ‘log’ scale. This helps in accommodating
acetylcholine and causes pupillary constriction wider dose range on a small graph paper and
and reduced intraocular pressure. Sulfonamides converts the hyperbolic curve (if arithmetic
act as antibacterial agents by competing with dose scale is used) into a sigmoid shape (if
p-amino benzoic acid and replacing it in the log dose scale is used). (Fig. 4.8)
synthesis of folic acid in bacteria; resultant Graded dose-response curve is useful for the
compounds are nonfunctional. assessment of the:
Protoplasmic Poisons: Antiseptics like 1. ED 50 from its linear segment. ED 50 is the
formaldehyde act as non-specific protoplasmic dose that produces 50% of the maximum
poison and kill the microorganism. response.
Figure 4.8 Graded dose-response curve

Pharmacodynamics 57
2. Potency of the drug. Potency refers to the people showing a particular response. Here the
amount of drug needed to produce a particular response is prefixed such as 20% fall in blood
response. The relative potency of drugs can be pressure from baseline. The response can also be
assessed by comparing the placement of the prefixed as ‘all or none’ response such as death
curve in relation to each other on horizontal or no death. It is a frequency distribution curve,
axis (Fig. 4.9). which shows frequency distribution of the doses of
3. Efficacy of the drug. Efficacy refers to the drugs required to produce a specified effect, i.e. the
maximal response that the drug can produce. percentage (%) of people that require a particular
Relative efficacy of drugs can be assessed dose to exhibit specified effect. A cumulative
by comparing the height of the curves (Fig. frequency distribution curve derived from quantal
4.9). dose response curve is a sigmoid curve (Fig. 4.10).
Quantal dose-response curve: This curve Quantal dose-response curve
provides an assessment of the relationship of 1. Does not tell about the magnitude of the
the different doses with the percentage (%) of response as the response is “prefixed”.
Figure 4.9 Potency and efficacy
Figure 4.10 Quantal dose response curve

2. Is a frequency distribution curve and indicates
the number of subjects (frequency) showing a
“prefixed” response to a certain dose.
3. Provides information about the individual
variations within a group.
4. Provides information about the optimal
therapeutic dose range to which most of
the patients show the desired response. The
corresponding range of plasma concentrations
of the drug is called its “therapeutic window”.
5. Can be converted to a cumulative frequency
curve by plotting the doses on the horizontal
axis and the cumulative percentage of
individuals showing prefixed response on Figure 4.11 Therapeutic index
vertical axis. Cumulative percentage for a
certain dose is calculated by summation of FACTORS AFFECTING DRUG
the percentage of individuals responding to it RESPONSES
and to all doses below this dose. It is a sigmoid
curve that allows calculation of ED50 and LD50. Drug Related Factors
6. Can be used to calculate ED50 which indicates
the dose that is effective in 50% of the The dose and the dosage form: The dose, i.e.
subjects. LD50 is the dose, which is lethal to the absolute amount of drug administered and
50% of the experimental subjects. the dosage form, i.e. the method or the form in
which the drug is administered, both modify the
drug responses. Increasing the amount of drug
MEASUREMENT OF DRUG SAFETY administration increases the risk of toxicity, more
so in case of drugs with narrow therapeutic margin.
The aim of drug therapy is to produce desired The dosage form needs to be selected according to
beneficial therapeutic effects without producing the pathological state to obtain optimum response.
hazardous effects. “Therapeutic index” is For example, sustained release preparations
an indicator of relative safety of drug and is provide a longer duration of action.
calculated as below (Fig. 4.11): The route of administration: The drug
TI = LD50/ED50 responses vary according to the chosen route of
administration. For example, inhaled salbutamol
Larger the LD50 as compared to ED50, safer
more quickly relieves the bronchospasm as
is the drug. “Certain safety factor” is a better
compared to orally administered salbutamol.
indicator of drug’s safety as it compares the dose,
which is effective in 99% of individuals with the The dosing interval: The dosing interval
dose that is lethal in 1% of the individuals. may greatly affect the therapeutic outcome.
For example: Once daily administration of
Certain safety factor (CSF) = LD1 /ED99
aminoglycosides is less likely to cause ototoxicity
Relative safety of a drug can also be expressed as compared to more frequent administration
in terms of “standard safety margin”, which is during the day.
calculated as below:
The duration of drug administration: The total
Standard safety margin = [(LD1 – ED99)/ duration of therapy influences the therapeutic
ED99]×100 outcome. For example, long-term glucocorticoid
Pharmacodynamics 59
therapy is likely to be associated with more Pathological state: The drug responses are
adverse effects as compared to short-term therapy. modified by individual’s metabolic, biochemical
The time of drug administration: The time and pathological status usually due to changes
of administration during the day can affect in drug disposition. For example, patients
the response to drugs. For example: Sedatives with impaired renal functions are more likely
produce sedation with smaller doses if given at to experience ototoxic adverse effects of
night as compared to when given during the day. aminoglycosides; patients with malabsorption
show decreased absorption of amoxicillin but
higher absorption of cotrimoxazole; hyperthyroid
Patient Related Factors individuals are relatively less sensitive to morphine
Age: The drug responses vary in relation to age but highly sensitive to sympathomimetics.
and the doses required for children are different Emotional and psychological state: Some
from the adult doses. In children, body surface individuals show therapeutic response to placebo
to mass ratio is considerably higher than that (pharmacologically inactive constituents)
of adults and accordingly doses for children are whereas others may collapse while entering
calculated on the basis of body surface area. As the operation theater and may show altered
it may be cumbersome to calculate body surface response to drugs due to altered emotional and
area for all patients, nomograms can be used that psychological state.
provide information about body surface area
based on height and weight.
MODIFIED DRUG RESPONSES
Body weight: Average adult dose is calculated,
based on the efficacy in 50% of adults, 18–65 Drug tolerance: Tolerance refers to the inability
years of age, and weighing about 70 kg. Therefore, to produce the response of same magnitude
abnormally lean or obese individuals require dose following repeated administration of a drug and an
adjustment. This is because the proportion of increase in dose is, therefore, required to produce
body water is higher in lean as compared to obese the same effect. Development of tolerance causes
individuals. the dose-response curve to shift parallel to the
Sex: Drug responses may be different in males and right. Intermittent dosing of some drugs like
females. For example: Barbiturates can produce cocaine causes increased responsiveness over a
period of time and this phenomenon is known
excitation in females before sedation. Beta-blockers
as sensitization. Sensitization causes the drug-
reduce libido only in males. Pregnancy and
response curve to shift to left.
lactation may also require alteration in doses due to
Development of tolerance is a relatively
alterations in drug disposition. During pregnancy,
common phenomenon, often observed with
plasma albumin levels reduce but plasma α1-acid
drugs acting on the central nervous system. The
glycoprotein levels increase. Therefore, the fraction
tolerance may not develop to all pharmacological
of unbound form of the acidic drug increases but actions of a drug. For example, repeated use of
that of basic drug decreases. morphine results into development of tolerance
Genetic variations: Some individuals may have to its most pharmacological effects but not for
a drug response different from the normally miosis and constipation. Tolerance to a drug can
observed response due to genetic variations. be natural, acquired or cross tolerance.
For example, deficiency of the enzyme glucose- Natural tolerance is genetically determined
6-phosphate dehydrogenase predisposes to and is observed after the administration of
hemolytic anemia, deficient activity of pseudo first dose. For example, rabbits are tolerant to
cholinesterase predisposes to apnoea in response atropine, Blacks are tolerant to mydriatic action
to very small doses of succinylcholine. of sympathomimetics.
Acquired tolerance develops following repeated can not be obtained even after increasing the
administration of a drug in an individual who dose. Drugs like ephedrine and amphetamine act
was initially responsive to the drug. This type of by releasing catecholamines from storage sites.
tolerance can develop either due to alterations However, repeated administration of these drugs
in drug disposition (known as pharmacokinetic causes depletion of catecholamines from storage
tolerance) or due to adaptive changes in the sites without a chance of replenishment. Therefore,
target tissue (known as pharmacodynamic following repeated administration, these drugs fail
tolerance). Tolerance to some drugs results from to produce the same pharmacological response.
both the pharmacokinetic and pharmacodynamic Prolonged exposure to nitrates also causes
alterations. development of tolerance as is the case in workers
Pharmacokinetic tolerance results when the exposed to nitroglycerine. These workers develop
drug reduces its own absorption, induces its headache at the beginning of the week due to
own metabolism or increases its own excretion, exposure to nitroglycerine but as the exposure
thereby requiring larger doses to produce continues during the week, headache disappears by
similar pharmacological effects after repeated Friday due to tachyphylaxis. However, when the
administration. For example, alcohol reduces its workers return to work on Monday after staying
own absorption after repeated consumption due away from nitroglycerine during the weekend, the
to thickened gastric mucosa, barbiturates induce headache reappears. Tachyphylaxis is rarely seen
the metabolizing enzymes and increase their in clinical practice as the repetitive administration
own metabolism, amphetamine promotes its own over a short period of time is not customary.
excretion after repeated administration as a result Cross tolerance can develop among the drugs
of acidification of urine due to reduced food intake belonging to the same category. For example,
and development of ketosis. The log plasma people tolerant to morphine are also tolerant to
concentration-response curve after development heroin.
of pharmacokinetic tolerance remains unchanged Drug interactions: Concurrent administration
as the increased dose compensates of the losses of two or more drugs may lead to modified drug
in the process of drug disposition, while the response. The modified drug response may appear
relationship between plasma drug concentration as a summative effect, additive effect, synergistic
and response remains unchanged. effect or antagonistic effect.
Pharmacodynamic tolerance develops due Summation of the drug responses is observed
to altered reactivity of the target tissue. After when two drugs administered concurrently
repeated administration, the response of the target produce same effect by acting through two
tissue is less despite the same plasma level. Hence, different mechanisms. Aspirin and codeine both
to obtain the same degree of response higher produce analgesia but act through different
plasma concentration is required as compared to mechanisms. Therefore, the degree of analgesia
initial plasma concentration. This is reflected by produced by concurrent administration of
the shift of log plasma concentration-response aspirin and codeine is equal to the sum of
curve to right. Some of the drugs that cause analgesic effects produced by each of them when
pharmacodynamic tolerance include morphine, administered individually.
nicotine, caffeine. Additive effect is also the sum total of the
Acute tolerance or tachyphylaxis refers to individual responses when two drugs are
development of the acute tolerance following administered concurrently. However, the two
rapid, repetitive administration of a drug at short component drugs produce the same effect by
intervals. Tachyphylaxis appears quickly after acting through same mechanism. For example,
repetitive doses and the original drug response aspirin and paracetamol.
Pharmacodynamics 61
Synergistic effect is observed when the response Pharmacokinetic antagonism is observed when
following concurrent administration of two drugs is one drug alters the absorption, metabolism
more than the sum total of their individual effects. or excretion of other drug, if coadministered.
The outcome of the synergistic effect may be in Phenytoin reduces the efficacy of warfarin by
the form of potentiation of activity, prolongation inducing cytochrome enzymes and enhancing its
of the duration of action or both. For example: metabolism.
combination of sulfamethoxazole and trimethoprim
Pharmacodynamic antagonism between two
is bactericidal although each of these drugs is
drugs is receptor mediated. As defined earlier,
bacteriostatic when administered individually.
antagonists have affinity for the receptor but no
This synergism is attributed to sequential action
intrinsic activity. They occupy the receptor and
of the two drugs on two different steps in the
same metabolic pathway for bacterial folic acid do not allow agonist to interact with it, thereby
synthesis. Hypertensive crisis observed after co- blocking the action of agonist. The receptor
administration of tyramine and monoamine oxidase mediated antagonism may be of the following
inhibitors (MAOI) is also an example of synergistic types:
effect. MAOIs inhibit metabolism of tyramine, 1. Reversible (competitive or equilibrium type)
which is then available in large quantities to release antagonism: The antagonist competes with
catecholamines causing hypertensive crisis. the agonist for the same receptor type and
Antagonism is observed when the response binds with it reversibly. However, if the
following concurrent administration of two concentration of agonist is increased the
drugs is less than the sum total of their individual antagonism may be overcome and maximal
effects. Antagonistic effects may be due to effect can be achieved, i.e. the antagonism
chemical antagonism, physiological antagonism, is surmountable. This is because the binding
pharmacokinetic antagonism or pharmacodynamic of antagonist is reversible and it dissociates
antagonism. easily from the receptors, which gradually
Chemical antagonism appears due to chemical become occupied by increasing concentration
interaction between two drugs. For example, of agonist along with the spare receptors.
tetracyclines are chelated by divalent cations This establishes a new equilibrium and
in antacids, thereby reducing the absorption hence is also known as equilibrium type of
of tetracycline. Negatively charged heparin is antagonism. As a higher quantity of agonist
antagonized by positively charged protamine, is required to produce the same effect in
which is used to terminate the action of heparin. the presence of antagonist, ED50 increases.
Antacids act simply by neutralizing the acid in Presence of reversible antagonist causes the
stomach. Deferoxamine facilitates excretion of agonist dose-response curve to shift in parallel
iron by chelating with it.
to right (Fig. 4.12). For example, atropine acts
Physiological antagonism refers to counter as a competitive antagonist of acetylcholine
balancing the opposite actions of two drugs on at muscarinic receptors.
the same physiological system. This antagonism 2. Irreversible (non-equilibrium type) anta
results from opposite responses and the ability of gonism: Irreversible antagonism is observed
each drug to produce its own effect is uninhibited. when the antagonist binds with the same
For example: Effect of CNS depressants is receptor as the agonist but this binding
antagonized by stimulants. Vasoconstrictors with receptor is irreversible due to covalent
antagonize the effects of vasodilators. bonds. The strong covalent bonds make
Figure 4.12 Shifting of agonist dose-response curve in Figure 4.13 Shifting of agonist dose-response curve in
presence of reversible antagonist presence of irreversible antagonist
the antagonist dissociate very slowly or verapamil blocks Ca++ channels and, therefore,
not at all from the receptors. Therefore, blocks norepinphrine-induced myocardial
by increasing the concentration of agonist, contraction without interacting with the β
antagonist occupancy does not change to receptors.
establish a new equilibrium (non-equilibrium 4. Negative antagonism: These antagonists
type) and hence the antagonism can not be occupy the receptors and produce effects
surmounted (insurmountable). As the higher opposite to that of agonists. For example,
concentration of agonist fails to overcome negative antagonism of β-carbolins at
the antagonism, maximal effect can not be benzodiazepine receptors.
achieved and the agonist dose-response curve
shifts down and to the right in the presence of
irreversible antagonist (Fig. 4.13). Example; OUTCOMES OF MULTIPLE DRUG
irreversible inhibition of acetylcholinesterase THERAPY
by organophosphate compounds. Some
antagonists like phenoxybenzamine may Multiple drugs are often administered in clinical
not exhibit typical feature of irreversible practice. This can be done either as concurrent
antagonism initially due to smaller receptor administration of more than one drug or as a
occupancy by the antagonist and availability fixed dose combination of more than one drug in
of spare receptors to agonist. However, a single dosage form. The outcome of the multiple
eventually with increasing concentration of drug therapy may be in the form of:
antagonist, typical features of irreversibility i. An adverse effect due to reduced efficacy or
are observed. increased toxicity of one of the drug due to
3. Non-competitive antagonism: This type of the presence of another. This type of effect
antagonism is observed when the antagonist is further discussed in the next section.
binds at a site other than the receptor for ii. A beneficial effect due to enhanced efficacy
agonist. This binding alters the receptor or reduced toxicity of one of the drug due
configuration so that it can no longer bind with to the presence of another. For example,
the agonist. Alternatively, the antagonist may combination of levodopa with carbidopa
block a particular step in the chain of events increase the availability of dopamine in
leading to agonist response. For example, brain.
Pharmacodynamics 63
iii. Interference with the diagnostic laboratory Expected Adverse Drug Reactions
tests. For example, salicylates give a positive (Type A–ADRs)
test for urine sugar, estrogens cause a false
positive rise in serum thyroxin values. These are predictable adverse drug reactions that
are related to pharmacological actions of the drug
Adverse Effects due to Drug-Drug and are dose-related.
Interactions Side-effects are undesirable but unavoidable
adverse effects observed with the therapeutic
The drug-drug interactions manifesting in the doses of drugs and are mild and dose-related.
form of reduced efficacy or enhanced toxicity For example, promethazine when used for anti-
may be observed in vitro or in vivo. allergic action also causes sedation, dicyclomine
In vitro drug-drug interactions occur due to relieves abdominal pain but also causes dry
mixing of incompatible drugs prior to admin mouth.
istration. For example, mixing penicillin and Secondary effects are due to major pharmacological
aminoglycosides in the same syringe. action of drug and are predictable. For example,
In vivo drug-drug interactions occur due to baclomethasone inhalation causes oral candidiasis
pharmacokinetic or pharmacodynamic interaction. due to reduced local immunity, broad spectrum
Pharmacokinetic drug-drug interaction leading antibiotics predispose to superinfection by
to adverse effects can be due to: suppressing the intestinal bacterial flora.
i. Altered absorption: Reduced tetracycline Toxicity can occur due to exaggerated pharma-
action due to chelation with antacids. cological action such as due to overdoses or
ii. Altered distribution: Excessive warfarin prolonged use and is predictable. For example,
action due to displacement form protein bleeding due to high doses of heparin, nephro-
binding sites by sulfonamides. toxicity to aminoglycosides.
iii. Altered metabolism: Reduced efficacy of oral
contraceptives due to metabolizing enzyme Unexpected Adverse Drug
stimulation by rifampicin.
Reactions (Type B – ADRs)
iv. Altered excretion: Enhanced excretion
of barbiturates in alkaline urine and These are unpredictable adverse drug reactions
amphetamine in acidic urine. that are not related to pharmacological actions of
the drug and are not dose-related.
Pharmacodynamic drug-drug interactions
leading to adverse effects can be due to: Allergy or Immunologically mediated adverse
drug reactions occur due to prior exposure to drug
i. Additive or summative action: Digitalis +
propranolol cause severe bradycardia. that initiates an immunological response. It can
ii. Altered ionic balance: Diuretics increase be a type I immune reaction such as anaphylaxis;
digitalis toxicity by causing hypokalemia. type II immune reaction such as drug-induced
iii. Altered neuronal uptake of neurotransmitters: hemolysis; type III immune reaction such as drug-
Imipramine blocks action of clonidine by induced glomerulonephritis or type IV immune
inhibiting neuronal norepinephrine uptake. reaction such as drug-induced contact dermatitis.
Drugs within the same group often exhibit cross
allergy.
ADVERSE DRUG REACTIONS
Genetically determined adverse drug reactions are
Undesirable, untoward or adverse drug reactions observed due to single gene mutation leading to
can be classified into expected adverse drug qualitatively different drug response. For example,
reaction or unexpected adverse drug reaction. presence of atypical pseudocholinesterase causes
excessive response to succinylcholine; isoniazid 3. Vauquelin G, Van Liefde I. G protein-coupled
causes neurotoxicity in slow acetylators due to receptors: a count of 1001 conformations. Fund
accumulation; deficiency of glucose-6-phosphate Clin Pharmacol. 2005;19(1):45–56.
dehydrogenase predisposes to hemolysis by 4. Cecilia I, Calero CI, Vickers E, Cid GM, Aguayo
drugs with oxidizing properties like primaquine LG, von Gersdorff H, et al. Allosteric modulation
of retinal GABA receptors by ascorbic acid. J
and sulfonamides; individuals deficient in
Neurosci. 2011;31(26):9672–82.
uroporphyrinogen synthetase are at risk of
5. Zong H, Neubig RR. Regulator of G protein
developing attacks of intermittent porphyria signaling proteins: novel multifunctional drug
when administered wit h drugs like barbiturates targets. J Pharmacol Exp Ther. 2001;297(3):
or phenytoin. 837–45.
Idiosyncratic reactions occur in minority of 6. Caprioli J, Sears M. The adenylate cyclase
individuals and can be fatal at times. Their receptor complex and aqueous humor formation.
cause is undetermined. For example, malignant Yale J Biol Med. 1984;57(3):283–300.
hyperpyrexia in response to succinylcholine, 7. Crook RB, Riese K. Beta-adrenergic stimulation
aplastic anemia in response to single dose of of Na+, K+, Cl- cotransport in fetal nonpigmented
chloramphenicol. ciliary epithelial cells. Invest Ophthalmol Vis Sci.
1996;37(6):1047–57.
Carcinogenicity, i.e. ability of the drug to cause 8. Jumblatt JE. Prejunctional alpha 2-adrenoceptors
malignancy, is a known adverse effect with some and adenylyl cyclase regulation in the rabbit
drugs like estrogen, radio-isotopes. iris-ciliary body. J Ocul Pharmacol. 1994;10(4):
Teratogenicity refers to drug-induced birth 617–21.
defects. Drugs like thalidomide, penicillamine, 9. Bausher LP, Gregory DS, Sears ML. Alpha
warfarin, phenytoin, valproate and many others 2-adrenergic and VIP receptors in rabbit ciliary
are associated with teratogenic adverse effects. processes interact. Curr Eye Res. 1989;8(1):
47–54.
10. Caulfield MP, Birdsall NJM. International
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1271–6. Garland Science; 2002.pp 852–62.
ChapteR 5
Ophthalmic Formulations and Ocular
Drug Delivery
Overview Table 5.1 Function of excipients
Eye has unique anatomical and physiological 1. To act as solvent for active ingredient
characteristics. Administration of ophthalmic 2. To adjust required concentration
medications on the ocular surface or inside the 3. To adjust tonicity
eye requires specially formulated preparations 4. To adjust pH
that are compatible with ocular tissue. Ophthalmic 5. To prevent microbial contamination
formulations are developed to optimally deliver
6. To increase viscosity
the active pharmaceutical agent at the targeted
7.
To promote corneal/conjunctival adherence of
site in eye. The composition of formulations is active ingredient
designed in a way that allows easy administration
8. To increase corneal drug permeation
and effective drug bioavailability into the ocular
tissue with least amount of ocular irritation and 9. To increase solubility
toxic effects. It is desirable that ophthalmic 10. To stabilize the active ingredient and prevent its
decomposition
preparations are free from foreign particles and
microorganisms, have suitable pH, tonicity and
viscosity. Moreover, the preparations should be
stable and must have adequate shelf-life. EXCIPIENTS IN OPHTHALMIC
To achieve these properties in an ophthalmic
PREPARATIONS
formulation, appropriate selection of ingredients
other than the active pharmaceutical agent in Preservatives
appropriate quantities is of critical importance.1
These ingredients, known as excipients, are Treatment of various ocular diseases often requires
inactive, biodegradable and non-irritant. The patients to use topical medication multiple times
commonly used excipients in ophthalmic a day for short-term or at times for prolonged
formulations include preservatives, vehicles, period. To ensure the protection against the risk of
tonicity agents, buffers, antioxidants and contamination with microorganisms, preservatives
surfactant (Table 5.1). The use of excipients to are added to all non-surgical, multiple use
impart color, odor or flavor is prohibited. topical preparations. Antimicrobial preservative
in a multi-dose ophthalmic product prevent the associated with ocular irritation, dry eyes, damage
patient from administering microbiologically to epithelial surface and other adverse effects. The
contaminated product in the eye. The main criteria severity of adverse effects due to preservatives
for selecting a preservative are: depends upon the type of preservative used,
a. It should be effective at a low concentration its concentration, frequency of use during the
against broad spectrum of organisms day and total duration of use. Various types of
b. It should be soluble in the formulation preservatives used in ophthalmic preparations are
c. It should be compatible with the drug listed in Table 5.2.
packaging components
d. It should be effective over the shelf-life. Detergent Preservatives
The US Pharmacopoeia Preservative
Effectiveness Test (PET) requires inoculation of Detergents interact with the lipid components
preservative containing solution with 106 colony of the microbial cell membrane and alter its
forming units/mL (CFU/mL) of Staphylococcus permeability. Due to membrane instability,
aureus, Pseudomonas aeruginosa, Escherichia cell contents leak out causing cell death. The
coli, Aspergillus niger and Candida albicans. preservatives in this group include quaternary
Each organism is tested separately. Following ammonium compounds like benzalkonium
inoculation on day 0, survivor count is done on chloride, alcoholic and phenolic compounds and
day 7, 14 and 28. To pass the PET requirement, centrimonium.
preservative should be able to produce 1-log Benzalkonium chloride (BAK): It is the most
reduction on day 7, 3-log reduction on day 14 and commonly used preservative in ophthalmic
no increase in survivor count from day 14 to day medications. It is highly stable at wide range
28. Fungi should show no increase in survivor of pH and temperature. It has a wide range of
count from day 0 to day 28. antibacterial activity and is highly effective in
Addition of preservatives also prevents combating the common microbes contaminating
biodegradation and prolongs the shelf- the ophthalmic solutions. In antiglaucoma
life of the preparations. Although addition medications it is used in a concentration range
of preservatives provides protection against of 0.004–0.02%. BAK breaks the cell-cell
microbial contamination, their repetitive use is junctions in corneal epithelium and enhances drug
Table 5.2 Classification of preservatives used in ophthalmic formulations
Preservative group Chemical class Examples

Detergent preservatives Quaternary ammonium Benzalkonium chloride,
compounds Polyquaternium-1, Centrimonium
Alcohols Chlorobutanol
Phenols Methyl/propylparaben
Oxidizing preservatives Mercurial Thimerosal
Carboxylic acid Sorbic acid
Amidines Chlorhexidine
Transient preservatives (oxidizing Stabilized oxychloro complex (SOC), Sodium perborate
agents)
Ionic buffered preservatives Combination of boric acid, zinc, sorbitol and propylene glycol
Chelating agents EDTA
Ophthalmic formulations and ocular drug delivery 67
penetration into the anterior chamber. However, the time required to produce toxic effects is
the effects of BAK are cumulative and, therefore, longer than that due to BAK. Chlorobutanol has
repeated use over a prolonged period causes only limited use because of its lower efficacy
damage to corneal epithelium. The damaging and instability when stored over extended period
effects of BAK on corneal epithelial cells are at room temperature. It permeates through
dose-dependent causing cellular apoptosis at polyolefin plastic containers.
concentration as low as 0.0001% and necrosis at Parabens: There are esters of p-aminobenzoic
higher concentration. On repeated use BAK also acid and are especially effective against yeast
disrupts the lipid layer of tear film. Therefore, use and moulds. They have a wide spectrum of
of medication containing BAK should especially antibacterial activity and are unstable at a high
be avoided in patients with deficient tear film or pH. Parabens have been used as preservative in
corneal epithelial abnormalities. Long-term use ophthalmic solutions, suspensions and ointments.
in antiglaucoma medications can result in toxic Propyl paraben is most commonly used. Their
inflammation of ocular surface. In patients with aqueous solubility is relatively low and they may
superficial inflammation or corneal abrasion, cause ocular irritation. Parabens permeate through
simple measure of stopping all topical medication polyolefin plastic containers.
can promote healing.
Polyquaternium-1 (Polyquad®) is a derivative of Oxidizing Preservatives
BAK and acts in the same way as BAK. Initially, it The oxidizing agents are small molecules that
was used in contact lens solutions. The significant penetrate the microbial cell membrane and interfere
difference in the action of polyquad® as compared with the cellular functions by reacting with
to BAK is that although, it affects bacterial proteins, lipids and DNA. Oxidizing agents are less
cells but is repelled by corneal epithelial cells. toxic to ocular surface as compared to detergents.
Therefore, repeated use is less likely to damage The examples include thimerosal, sorbic acid,
the ocular surface than BAK. However, polyquad® chlorhexidine. Transient acting preservatives
reduces the density of conjunctival goblet cells sodium perborate and stabilized oxychloro
and its long-term use decreases production of the complex (SOC) are also oxidizing agents.
aqueous layer of tear film. Thimerosal: It is a mercury containing
Centrimonium: It has its antibacterial action preservative that was used extensively in topical
similar to BAK. The toxicity of centrimonium to preparations and vaccines. However, it was found
ocular surface is also similar to BAK and includes to be a common cause of allergy and its use in
keratinization and inflammatory infiltrates at vaccines was associated with high incidence of
the limbus and within the conjunctival stroma autism. Because of the safety concerns, use of
and epithelium. Although, it is a component of thimerosal in over-the-counter drugs was banned
some artificial tear solutions, it is primarily used in 1998.
as softener in hair treatment solutions due to its Sorbic acid: It is a natural organic compound.
antiseptic and cationic surfactant properties. It is Potassium sorbate has fungistatic and limited
also used as a fermentation aid, a dispersant and antimicrobial properties. It has been used
as preservative in antifungal creams. in ophthalmic medications and contact lens
Chlorobutanol: It has a wide range of solutions. Its antimicrobial efficacy is poor and
antibacterial action but is less effective than BAK. it is used in combination with other preservative.
It does not have surfactant action like BAK but At certain concentrations, the products of sorbic
causes bacterial cell lysis by damaging the lipid acid oxidation are known to discolor some
component of cell wall. Similar to BAK, it causes hydrophilic contact lenses. It can also cause
corneal and conjunctival cell damage, however, allergic reactions.
Chlorhexidine and polyhexamethylenebiguanide forms. It is a broad spectrum antimicrobial
have a broad range of antibacterial action like system. The ocular surface toxicity caused by
BAK. Additionally they are effective against these preservatives is significantly less than the
Acanthamoeba. They have poor fungicidal action. traditional preservatives and is almost comparable
They have been used in contact lens solutions. to that caused by preservative-free artificial
Unlike BAK, they do not cause significant tears. This preservative system has been used in
alteration in corneal permeability or the tear film travoprost formulation.
stability.
Chelating Agents
Transient Preservatives
Chelating agents like disodium EDTA have the
These are the newer oxidative preservative ability to bind with divalent metallic ions. EDTA
systems. These compounds do not accumulate and is added to ophthalmic preparations to enhance
upon exposure to tears dissipate into constituents the antimicrobial action of other preservatives
already present in the tear film such as Na+, Cl–, like BAK. It does not cause significant cellular
O2, and H2O. They have high antibacterial activity toxicity, however, allergic dermatitis may occur.
but significantly less cellular toxicity as compared
to traditional preservatives. Vehicles
Stabilized oxychloro complex (SOC): It is also
known as purite, is a component of a wide variety Ophthalmic solutions are prepared by dissolving
of ophthalmic medications such as artificial the active ingredient in an appropriate vehicle.
tears and antiglaucoma drugs. It has a broad Purified water is the vehicle of choice for
antibacterial, antiviral and antifungal action. this purpose in topical preparations as all the
Chemically it consists of chlorine dioxide, major therapeutic agents are water soluble
chlorite and chlorate. SOC dissociates into water, salts. The commonly used salt forms include
oxygen, sodium and chlorine free radicals when hydrochloride, nitrate, sulfate and phosphate.
exposed to light. The chlorine free radicals cause Salicylate, hydrobromide and bitartrate salts are
glutathione oxidation and inhibit microorganism also used. For acidic drugs like sulfonamides,
protein synthesis leading to microbial cell death. sodium salts are used. Non-aqueous liquids are
rarely used as they cause ocular irritation and poor
Sodium perborate: It is used in artificial tear
patient acceptability.
solutions. It alters protein synthesis within
bacterial cells by oxidizing cell membranes and
inhibiting membrane-bound enzymes. After Excipients to Enhance Ocular
instillation in eye, it converts into hydrogen Bioavailability
peroxide and then to oxygen and water. Hydrogen
Ingredients, other than those used to dissolve
peroxide effectively kills microorganisms.
the active ingredient are added to ophthalmic
formulations to enhance the ocular bioavailability
Ionic Buffered Preservatives of drugs. Such vehicles can enhance ocular
This is a newer class of preservatives that acts bioavailability by:
in the same way as oxidizing preservatives. An i. Increasing the corneal residence time: Visco
example in this category is a combination of sity enhancers and mucoadhesives, phase
boric acid, zinc, sorbitol and propylene glycol. transition vehicles (in situ gelling system).
Following instillation, contact with cations of ii. Increasing the corneal permeability of drugs:
tears converts these components into inactive Penetration enhancers
Exicipients That Increase Corneal Table 5.3 Mucoadhesive performance of several

polymers
Residence Time
Adhesive substances Performance
Viscosity Enhancers and Carboxymethyl cellulose Excellent
Mucoadhesives Carbopol Excellent
A large number of vehicles are used in ophthalmic Carbopol and hydroxypropyl Good
cellulose
formulations primarily to increase the drug’s
corneal contact time either by increasing the Carbopol base with white petrolatum Fair
viscosity of solution and/or by promoting its Carbopol 934 and EX 55 Good
adherence to corneal surface. Viscosity enhancers Poly (methyl methacrylate) Excellent
increase the thickness of tear film, reduce the tear Polyacrylamide Good
drainage and allow the drug to stay on corneal Poly (acrylic acid) Excellent
surface for a longer period. This increases the Polycarbophil Excellent
drug’s bioavailability as the time for which drug Homopolymers and copolymers of Good
stays on corneal surface increases. Hydrophilic acrylic
high-molecular weight polymers are used as Gelatin Fair
viscosity enhancers in concentrations that Sodium alginate Excellent
produce a viscosity of 5–100 cps. Use of viscosity
Dextran Good
enhancers in suspensions prevents particle
Pectin Poor
sedimentation between uses. However, initial
Acacia Poor
resuspension becomes more difficult due to high
viscosity. Mucoadhesives are the high-molecular Povidone Poor
weight electrically charged polymers.They bind Poly (acrylic acid) crosslinked with Fair
sucrose
with the conjunctival and corneal mucin layer,
stabilize the tear film and prolong the stay of drug
on corneal surface. Mucoadhesive performance
of several polymers is summarized in Table 5.3.
Polymers depending upon their loading to thick layer of medication on the cornea and
capacity deliver drugs in a controlled manner deposits on eyelids. High viscosity also makes the
over a prolonged period. This helps to achieve sterilization by filtration more difficult. Physical
steady state concentration at target sites without properties of vehicle are determined by molecular
significant fluctuations as is the case with other size, molecular weight, viscosity and presence of
formulations that provide pulsed drug delivery. salts, divalent cations and anions. Some of the
The polymers in controlled drug delivery systems commonly used polymers are discussed below.
are used either in the reservoir form or the matrix Cellulose derivatives are hydrophilic polymers.
form. In the reservoir form, the polymer forms a The commonly used agents in ophthalmic
coat around the active drug containing nucleus. preparations include carboxymethyl cellulose
In the matrix type, active drug is homogenously (CMC) and hydroxypropyl methylcellulose
mixed with polymer and forms covalent or (HPMC). CMC is a viscosity enhancer but in
hydrogen bond with polymer molecules. addition, due to its anionic charge, it promotes
The polymers generally used as inactive mucoadhesion and stabilizes tear film. The
vehicles with the active ingredients in artificial tear mucoadhesive property of CMC is significantly
solutions help to improve tear film stability in dry higher than other vehicles. HPMC is also a
eye conditions. There are several disadvantages viscosity enhancer like CMC. It increases the
of adding the polymers especially in high- tear film wetting time and significantly increases
viscosity solutions such as blurred vision due ocular retention time.
Polyvinyl alcohol (PVA) is a water-soluble Cyclodextrins are used to improve the solu
viscosity enhancer and is commonly used in a bility and drug delivery to corneal surface. They
concentration of 1.4%. The increase in viscosity consist of a lipophilic center to incorporate the
by 1.4% PVA is only half to that of 0.5% CMC. lipid soluble drugs and adhere to corneal surface.
Besides its use in ophthalmic preparations to Outer surface is hydrophilic consisting of 6–8
enhance viscosity and corneal residence time, it glucose units, which help to stabilize the tear film.
is also used for the treatment of corneal epithelial White petrolatum (60%) and liquid mineral
erosions. It is nonirritating and promotes healing oil (40%) mixture is used as vehicle in ointments.
of abrasions. This molecular complex melts at body temperature
Polyvinylpyrrolidone (PVP) is a polymer and releases the active drug. Water-miscible agent
having an average molecular weight in the range lanolin is added sometimes, which allows water-
of about 25,000–40,000. It is a thickening agent soluble drugs to be retained in the ointment.
that increases the corneal residence time of active Ointments are retained for a longer period in the
drug. As a lubricating agent, it is used in the conjunctival sac as they are cleared very slowly by
treatment of dry eyes. It helps in solubilizing some tear drainage. The nonpolar oil base of ointments
drugs like chloramphenicol. Ocular irritation is readily absorbed by precorneal and conjunctival
due to drugs like oxymetazoline reduces in the tear film. This allows increased corneal contact
presence of PVP. It is also used as stabilizer in time and prolonged drug delivery.
some ophthalmic suspensions like mefenamic
acid suspension. Phase Transition Vehicles
Sodium hyaluronate is a high molecular
weight polymer. When added to ophthalmic These are liquids that are converted to gel form
solution it increases viscosity. Due to its high when instilled into the cul-de-sac. The polymers
viscosity, it stabilizes tear film. After instillation, like lutrol FC-127 and poloxamer 407 undergo gel
repeated blinking reduces viscosity, an effect formation in response to change in temperature,
known as ‘shear thinning’. This property of i.e. at 37°C on the ocular surface. Cellulose
sodium hyaluronate is advantageous as thinning acetate phthalate is a polymer that forms gel when
of the solution due to blinking prevents feeling its native pH of 4.5 rises to 7.5 after instillation in
of ocular irritation. Several studies have shown eye. Gelrite is a polysaccharide, low-acetyl gellan
that addition of sodium hyaluronate to ophthalmic gum. It gels in the presence of mono or divalent
solution prolongs the corneal residence time of cations normally present in tears. These gel
some drugs and improves their bioavailability. forming vehicles increase the corneal residence
Polyacrylic acids such as carbopol gels time of the drug and prolong the drug’s duration
are used in ophthalmic solutions to enhance of action. Xanthan gum, a heteropolysaccharide
corneal residence time of the drug. Enhanced is also used as phase transition vehicle to prolong
viscosity of polyacrylic acid containing solutions corneal residence time of drugs.
decreases by increased shear rate due to blinking
and eye movement. Reduced viscosity reduces Excipients that Increase Corneal
ocular irritation and provides better patient Permeability
acceptability. Moreover, polyacrylic acids are
Penetration Enhancers
good mucoadhesives at the ocular surface.
Polyionic vehicles like poloxamer 407 have Penetration enhancers act by temporarily increasing
been used to improve the delivery of lipophilic the corneal permeability for drugs. The alteration
drugs like steroids. Poloxamer has a lipophilic in corneal epithelial permeability occurs either due
nucleus, which helps to deliver the lipid soluble to changes in cell cytoskeleton and tight junctions
drug to corneal surface and hydrophilic end chains to allow better paracellular absorption or due to
that stabilize the tear film. interaction with lipid or protein components of cell
membrane to allow better transcellular permeation. without affecting the stability of solution. Majority
Chelating agents, preservatives, surfactants and of ophthalmic drugs are salts of weak bases and are
bile salts exhibit these properties but are associated stable at acidic pH. Instillation of acidic solution is
with corneal toxicity. generally without much stinging sensation if the
induced tearing quickly restores the pH of instilled
Tonicity Agents formulation equal to that of tears. The choice of
buffer system to be used is of critical importance
The ophthalmic solutions require adjustment in this regard. Preferably the buffer system should
of tonicity close to that of natural tears. The be of low-capacity so that it can maintain the acidic
tonicity of natural tears is equal to that of 0.9% pH of formulation for stability but upon instillation
saline. Generally, a range of 0.5 to 2% saline allows tears to neutralize it. High capacity buffers
equivalent tonicity is well tolerated by eye. resist the pH adjustment by tears and cause stinging
Most formulations aim to achieve 0.7 to 1.5% due to presence of acidic solution on ocular surface
saline equivalent tonicity. Commonly used for a longer period. The corneal endothelium is
tonicity agents are NaCl, KCl, dextrose, buffer much less resistant to damage by pH variations
salts, glycerin, propylene glycol and mannitol. as compared to epithelium. Therefore, the pH
Hypertonic solutions induce lacrimation causing adjustment of intraocular formulation is extremely
immediate dilution and enhanced drainage of the important. The commonly used buffers include
drug. Hypotonic solutions are sometimes used phosphate, borate and acetate.
in the treatment of dry eyes when the tonicity
of natural tears is abnormally high. Hypertonic Surfactants
solutions are used to relieve corneal edema.
Surfactants in low concentration are added
to increase the dissolution and dispersion
Buffers of substances like steroids in solution. They
The adjustment of the pH of the ophthalmic also improve the clarity of solution. Nonionic
formulation is necessary not only for patient comfort surfactants are preferred over ionic as they are
and safety but it also stabilizes the formulation, less toxic. Polysorbate 80 (Tween 80) is used in
improves solubility, enhances preservative action ophthalmic suspensions. Polyoxol 40 stearate
and increases bioavailability. The pH of normal and propylene glycol are used to solubilize
tears is 7.4. Therefore, it is desirable to have the a drug in anhydrous ointment. Some agents
same pH for ophthalmic formulations. However, prevent drug loss due to adsorption to container.
this is often difficult and some drugs precipitate at Other examples of surfactants include polyoxol
this pH and many are unstable. The pH is, therefore, 40, hydrogenated castor oil and cremophore EL
adjusted in a way that it is as close to 7.4 as possible (Table 5.4).
Table 5.4 Wetting and solubilizing agents used in ophthalmic formulations
Benzalkonium chloride Polyoxyl 50 stearate Polysorbate 80

Benzethonium chloride Polyoxyl 10 oleyl ether Sodium lauryl sulfate
Cetylpyridinium chloride Polyoxyl 20 cetostearyl ether Sorbitan monolaurate
Docusate sodium Polyoxyl 40 stearate Sorbitan monooleate
Nonoxynol 10 Polysorbate 20 Sorbitan monopalmitate
Octoxynol 9 Polysorbate 40 Sorbitan monostearate

Poloxamer Polysorbate 60
Antioxidants Physicochemical properties of drugs, such as

lipophilicity, solubility, molecular size and shape,
Antioxidants are added to ophthalmic formulations drug charge and degree of ionization, affect the
containing epinephrine and other oxidizing drugs. mechanisms and rate of transport. Lipophilic
They stabilize the formulation and prevent its drugs are transported through the transcellular
degradation. Sodium sulfite and metabisulfite are pathway, while hydrophilic drugs penetrate
used in a concentration of 0.3% in epinephrine through the paracellular pathway. The optimum
hydrochloride and bitartrate solutions. Other apparent partition coefficient in octanol/buffer
antioxidants used are sodium thiosulfate, ascorbic (pH 7.4) for corneal drug penetration was found
acid and acetylcysteine. to be in the range of 100 to 1000. The stroma is a
highly hydrophilic tissue, which mostly consists
of water. Due to a relatively open structure,
OPHTHALMIC DRUG DELIVERY
drugs with molecular size up to 500000 can
SYSTEMS diffuse through normal stroma. Tight junctions
are present in corneal endothelium but they are
Critical Barriers in Ocular not as tight as those in the epithelium. It was
Therapeutics estimated that drugs with molecular dimension
Topical instillation remains the first choice in up to about 20 nm can diffuse through normal
ocular drug delivery. However, due to the innate endothelium. In addition to the physical barriers,
protective structure of the eye the bioavailability ocular tissues contain metabolic enzymes, such as
of an instilled drug is generally low. The cornea esterases, aldehyde and keton reductases, which
forms a non-vascularized barrier, which is may degrade and reduce the efficacy of the drugs.
As a result of these anatomical and physiological
highly resistant to passive diffusion of ions and
constraints, after topical application, a major
molecules. It has a smaller surface area compared
fraction of the administered drug is lost by
to conjunctiva, which has a leakier epithelium
different mechanisms, resulting in very low
than the cornea. The conjunctiva not only acts
ocular bioavailability (Fig. 5.2). Systemically
as a protective covering but also functions as a
administered drugs also fail to achieve adequate
passive physical barrier.2 level in ocular tissue due to blood-ocular barriers.
The unique features of anatomical structures For transconjuctival influx and efflux,
and physiological barriers for permeation transporters such as P-glycoprotein, are known
and distribution in ocular tissue for topically to play an important role. There is a significant
applied drugs are represented in Figures 5.1 systemic absorption via lymphatic and blood
and 5.2. Relevant details are discussed in vessels. The lacrymal film secreted by the
Chapter 3. Despite all the inconveniences goblet cells of the conjunctiva not only cleanses,
of topical administration, this non-invasive hydrates, lubricates and serves as a defense
method continues to be a favored route of drug against the pathogens; but also, it involves an
administration in clinical practice. Thus, the additional obstacle to any drug penetration. The
development of topical ocular drug delivery lacrymal film is a dynamic fluid and undergoes
systems with advances to overcome these a constant renewal and, therefore, limits the
constraints currently represents a promising time of residence of the drugs on the surface
approach for the treatment of ocular diseases.3 of the eye.
Figure 5.1 Compartmentalized scheme of drug penetration across human cornea, conjunctiva, and
sclera into anterior and posterior segment of the eye
Topical drug delivery systems 2. Control the release of drugs.

3. Achieve a targeted delivery.
ocular drug delivery systems represent an Liquid and semiliquid forms are the most
approach to control and optimize the drug delivery commonly used ophthalmic drug delivery
to target tissues in the eye. An optimum topical systems. They are cheap, convenient to use and
ocular drug delivery system would be one which can be easily self-administered. However, these
can be delivered in eyedrop form without causing devices do not provide continuous drug delivery
blurred vision or irritation and, which would need over a prolonged period, which is possible with
no more than one to two applications each day.4 solid drug delivery devices that are comparatively
The three major goals in developing topical expensive and inconvenient at times. Patient
ocular drug formulations are: acceptability in general is higher for liquid and
1. Enhance the drug permeation. semiliquid preparations.
Figure 5.2 Constraints in topical ophthalmic drug delivery
Conventional Ophthalmic Dosage preservatives. Other excipients are added to

Forms5 enhance corneal penetration. Corneal penetration
enhancement can be achieved best by increasing
Aqueous solutions: Most ocular diseases are solution concentration, increasing corneal contact
treated with topical application of solutions time by adding viscosity enhancers, selection of
administered as eyedrops. A homogeneous drug with appropriate pKa and offering optimal
solution offers many advantages including the lipid solubility with the use of appropriate buffers.
simplicity of large scale manufacture. The factors The stability of ophthalmic solutions and
that must be taken into account while formulating other dosage forms determines the shelf-life and
aqueous solution include selection of appropriate expiration dating of the product. The drug product
salt of the drug substance, solubility, therapeutic is analyzed for physical (pH, osmolality, viscosity,
concentration required, ocular toxicity, pKa, the color and appearance of the product), chemical
effect of pH on the solubility and stability, tonicity, (assays for the active and degradation product and
buffer capacity, viscosity, compatibility with other preservative efficacy of the product and bioburden
formulation ingredients, choice of preservative, of all compounds) and microbiological parameters
ocular comfort and ease of manufacturing. throughout the shelf-life.
Generally aqueous ophthalmic solutions Suspensions: Suspensions form an important part
are manufactured by dissolution of the active of the ophthalmic dosage forms and offer distinct
ingredient and other inactive ingredients advantages. Hydrophobic ophthalmic drugs have
followed by heat sterilization or sterile filtration. limited solubility in water. Formulation of a sterile,
Sterility of solution is further ensured by adding preserved, effective, stable and pharmaceutically
elegant suspension is more complex and Packaging and Storage
challenging compared to conventional ophthalmic
solutions. Particle size of the active agent plays a The packaging of solutions and suspensions in an
key role in physical stability and bioavailability appropriate container is important in determining
of the drug product. The rate of sedimentation, the delivery of right amount of drug to the ocular
agglomeration and resuspendability are affected surface. Conventional eyedroppers deliver the
by particle size. Generally, the average particle drops of the size ranging from 50–70 µL. Newer
size is less than 10 mm. The most efficient packages deliver antiglaucoma medications in
method of producing such particle size is by the drops of the size 25–56 µL. Many ophthalmic
dry milling. Other methods of particle size medications are now dispensed in bottles with
reduction include micro-pulverization, grinding, especially constructed dropper tip that allows
and controlled precipitation. An ophthalmic control over the volume of each drop delivered.
suspension contains many excipients such as These dropper tips consist of an outer chamber
dispersing and wetting agents, suspending agents, that delivers the drop connected with an inner
buffers and preservatives. The selection of buffers chamber through an aperture. The design allows
and preservatives for suspension are similar to only one drop to enter the outer chamber with
that of ophthalmic solutions in almost all aspects each squeeze. A change in the outer diameter
except that they must also be compatible with the and platform width allows desired changes in
flocculating systems.6 the size of drops. Many ophthalmic solutions are
The formulation of ophthalmic suspension now packaged in unit-dose dispensers to avoid
includes sterilization of the micronized active toxicity due to added preservatives in multi-dose
vials. The unit-dose dispensers contain about 0.1
drug either by dry heat, exposure to gamma
to 0.6 mL of the solution and as there is no added
irradiation or ethylene oxide or in some cases
preservative, they are for short-term use.
steam sterilization of concentrated slurry followed
Various ophthalmic solutions and suspensions
by ball-milling. Major steps of formulating an
are packaged in containers that do not differ much
ophthalmic suspension are: in size and shape. Therefore, it is important to
a. Preparation of a dispersion of the drug follow standardized labeling so as to facilitate
b. Preparation of the structured vehicle, followed clear identification of medications. Moreover,
by addition of the drug dispersion each time a medication is used the name on the
c. Addition of the other adjuncts, and label must be confirmed. The recommended
d. Homogenization. color coding of various ophthalmic solutions
The advantages and disadvantages of using and suspension is shown in Table 5.6. It is also
solutions and suspension are listed in Table 5.5. important to look for the expiry date on the
Table 5.5 Advantages and disadvantages of solutions and suspensions

Formulation Advantages Disadvantages
Solutions •• Easy instillation •• Short corneal contact time
•• No interference with vision •• Contamination
•• Ocular irritation less than suspension/ •• Mechanical injury during instillation
ointment
Suspensions •• Easy instillation •• Require adequate shaking before use
•• No or minimal interference with vision •• Inconsistent drug delivery
•• Corneal contact time longer than solution •• May cause clogging of dropper tip
•• Ocular irritation
•• Contamination
•• Mechanical injury during instillation
label. The medications are not recommended can be applied to each eye on an alternating
for use after the expiry date as the ingredients schedule. This helps to minimize discomfort due
may break down leading to loss of efficacy to blurred vision. The discomfort can also be
or toxicity. Eye drops if stored in refrigerator avoided by applying the ointment to lid margins,
may have a prolonged shelf-life, although, the lashes and canthi.
degree of ocular irritation is not affected by Use of ointments provides prolonged corneal
cold storage. Application of cold eye drops may contact time as compared to solutions because
help some patients to ensure proper instillation. of two reasons.1 After application to inferior
Some ophthalmic preparations are better stored fornix, ointments also spread over lid margin,
in inverted position. This allows air bubbles lashes and surrounding skin depending upon
to escape on the top of the liquid and avoids the amount applied and extent of tearing due
interference by air bubbles while using the to irritation. The ointment that spreads over lid
medication. margin keeps on releasing the drug over cornea
Ointments: Ointments are a common form of and thus enhances the drug-corneal contact time.2
topical ocular drug delivery. They are applied The nasolacrimal drainage of ointments is slower
to inferior fornix with patient looking up and lid than that of solution, allowing drug to stay in
retracted. Alternatively, especially in children, contact with corneal surface for a longer period.
ointments can be applied with the help of a cotton Slower nasolacrimal drainage of ointments is also
bud to the lid margin, lashes, medial and lateral responsible for reduced systemic side-effects as
canthus. If the patient is required to use ointment compared to solutions.
in conjunction with solution, solution must be The ointment can be applied postoperatively
instilled first because once applied ointments do only if the corneal wound is tightly secured.
not allow the solutions to reach the precorneal The ointment can be used in the treatment of
tear film due to their waxy vehicle. Following superficial corneal ulcers involving only the
application, ointments melt at body temperature epithelial surface and with clean margins. Corneal
and release the components, which spread over ulcers with large flap-like overhanging margins,
cornea. The spread of thick layer of medication those with impending perforation and open
over cornea may cause blurred vision. Therefore, conjunctival lacerations should not be treated
ointments are preferably used at bed time to avoid with ointment due to the risk of entrapment of
the discomfort due to blurred vision. If a day-time the ointment.
application is required the amount instilled should A typical formulation (Table 5.7) of an
be kept at minimum. Additionally, the ointment ophthalmic ointment includes micronization
and sterilization of the active agent by dry
Table 5.6 Standard colors for drug labeling and heat, ethylene oxide irradiation or gamma
bottle caps irradiation. Antimicrobial preservatives like
chlorobutanol or parabens are dissolved in
Drug Class Standard Color a mixture of molten petrolatum and mineral
b-blockers Yellow, blue, both oil and cooled to about 40°C with continuous
Mydriatics and cycloplegics Red mixing to assure homogeneity. Sterilized and
Miotics Green micronized drug is then added aseptically to the
Carbonic anhydrase inhibitors Orange
warm sterilized petrolatum/mineral oil mixture
with continuous mixing until the ointment is
Nonsteroidal anti-inflammatory Grey
drugs
homogeneous. The ointment is then filled into
presterilized ophthalmic tubes.
Steroids Pink
Anti-infective agents Brown
Gels: Ophthalmic gels consist of gelling-agent
with high water binding affinity. Like ointments
Table 5.7 Formulation components for various dosage forms7
Component Solution Suspension Ointment Gel Oral/injection Insert
Drug * * * * * *
Drug carrier # # # # # #
Water * * - * * #
Buffer/acid and base * * - * * -
Preservative * * # * * -
Tonicity agent # # - # # -
Salts # # - # # -
Viscosifier # # - - # -
Bioadhesive agent # # - # # #
Phase modifier - - - * # -
Suspending agent - # - # -
Solubilizer # - - # # -
Permeation enhancer # # - # # #
Wax/petrolatum/oil - - - - - #
Cross-linked polymer - - * - - *
* Component is included or generally included in the formulation, # Optional
they melt at body temperature to release the strong non-covalent bonds with the mucin
components. The blurred vision is much less coating on the biological membranes and thus
as compared to ointments and they can be used remain in place as long as the mucin is present.
during the day-time. Pilocarpine and some Bioadhesive polymers are usually macromolecular
artificial tear preparations are available in gel hydrocolloids with numerous hydrophilic
form. functional groups. Most of the bioadhesives
used in drug delivery systems are composed
Nonconventional Ophthalmic Drug of synthetic mucoadhesives, including water-
Delivery Systems soluble polymers that are linear chains and water
insoluble polymers that are swellable networks
Polymeric Gels joined by cross-linking agents. Typically, these
polymers have high molecular weight molecules
Polymeric gels are classified into two distinct
(5000–10000 Da), which cannot cross biological
groups: preformed and in situ forming gels, both
membranes and include cellulosic components
of which improve bioavailability and decrease the
like sodium carboxymethyl cellulose (CMC),
side-effects induced by the systemic absorption
or polyanion bioadhesives like polyacrylic acid
of topically applied ophthalmic drugs.
(PAA).
Bioadhesive Hydrogels: The efficacy of opht Hyaluronic acid (HA) is a high molecular
halmic semisolid hydrogels is mostly based weight biological polymer consisting of linear
on an increase of ocular residence time, via polysaccharides present in the extracellular
enhanced viscosity and mucoadhesive properties.8 matrix. In the eye, HA is present in the vitreous
Bioadhesive polymers are capable of forming body and in low concentrations in the aqueous
humor. HA has been shown to be a potent is raised to the eye temperature (33–34°C)
mucoadhesive polymer. Some investigations from a critical temperature (16°C). Cellulose
with the use of exogenous HA had led to the acetophtalate (CAP) is a polymer with potentially
characterization of this compound as a topical useful properties for sustained drug delivery to the
pseudoplastic polymer that guarantees a better eye. Latex is a free running solution at a pH of
protection of the cornea. 4.4, which undergoes coagulation when the pH is
With viscous Newtonian systems, the viscosity raised by the tear fluid to pH 7.4. In situ activated
is independent of the shear rate. With increasing gel-forming system has also been used with gellan
viscosity, beyond a limit, there is no further gum, an anionic extracellular polysaccharide,
increase of the residence contact time and secreted by Pseudomonas elodea. Gellan gum
blinking becomes painful. On the other hand, non- (Gelrite) formulated in aqueous solution, forms
Newtonian formulations that display pseudoplastic clear gels in the presence of mono or divalent
properties can acquire a viscosity decrease with cations typically found in the tear fluids.
increasing shear rate by blinking and ocular To reduce polymer content, a combination of
movement. Shear rates associated with normal polymers, methylcellulose or HPMC and carbopol
blinking are quite important (ranges from 0 s-1 at may also be used. The former polymers exhibit
rest to 10000 s-1 during blinking). Pseudoplasticity thermal gelation and the latter pH-dependent
is thus interesting because it offers significantly gelation. The formulation thus formed is an easy
less resistance to blinking and shows much greater flowing formulation, which reversibly forms a
acceptance than viscous Newtonian formulations. gel in a sol-gel transition between 25 and 37°C,
Moreover, it is widely accepted that such non- as well as with a pH increase from 4 to 7.4. A
Newtonian vehicles as HA, and polyacrylic acids possible mechanism of the thermal effect could
are more effective than Newtonian formulations be a decrease in the degree of hydration of
containing polyvinyl alcohol or cellulose in a methylcellulose and a conformational change
similar viscosity range. Furthermore, viscosity of the polymer structure with the increase in
and rheological behavior are not the only factors temperature. The acidic solution of polyacrylic
to be considered. Mucoadhesive and wetting acid can transform into a gel upon an increase in
properties are also critical parameters to take into the pH by the buffering action of tear fluid.
consideration during ophthalmic formulation.
In situ activated gel-forming systems: This can be Colloidal Systems
described as viscous liquids that upon exposure to A liquid retention drug delivery system, can be
physiological conditions will shift to a gel phase. represented by a colloidal system containing
The principal advantage of this formulation is drug in carrier. Colloids consist of small particles
the possibility of administering accurate and ranging in size from 100–400 nm suspended
reproducible quantities, in contrast to already in aqueous solution. Particle size above 10 µm
gelled formulations and promoting precorneal gives a foreign body sensation. The particles
retention. Three methods have been employed to consist of polymer complexed with the drug.
cause phase transition on the eye surface: change Colloidal carriers act by increasing the specificity
in viscosity can be triggered by a change in of the action of drugs towards a specific target,
temperature, pH, or electrolyte composition.9-12 . facilitate the bioavailability of drugs through
Sustained drug delivery can be achieved by biological membranes and protect a drug against
use of a polymer that changes from sol to gel at enzyme inactivation. Corneal epithelial cells
the temperature of the eye. The poloxamers are take up the particles by endocytosis and act as
polyols with thermal gelling properties. Their reservoir from which the drug is slowly released
solution viscosity increases when temperature in the surrounding tissue. Thus the need to
incorporate a viscous medium is eliminated. negative and neutral surface charge. Retention
These preparations are easy to administer and of liposomes on the corneal surface perhaps
require less frequent administration. Colloidal represents the major challenge for effective ocular
forms include liposomes, nanoparticles, niosomes, drug delivery. Several studies, have shown that
microemulsions, etc. introducing a positive surface charge on vesicles
can prolong precorneal retention time, enhance
Liposomes: These are the more recent additions
ocular bioavailability and ultimately increase
to drug delivery systems in ophthalmology.
the duration of pharmacological effect. This may
They offer a promising avenue to fulfill the need
be attributed to the ability of liposomes with a
for an ophthalmic drug delivery system that
positive surface charge to have a more stable
has the convenience of a drop, but will localize adsorption because corneal epithelium is thinly
and maintain drug activity at its site of action. coated with negatively charged mucin.
Liposomes are microscopic vesicles composed of Another strategy used to retard the precorneal
membrane-like lipid bilayers surrounding aqueous drainage rate of liposomes has been to coat
compartments. They can be multilamellar, small vesicles with mucoadhesive polymers. Liposomes
unilamellar and large unilamellar vesicles dispersed in carbopol solutions demonstrated
depending upon the number of lipid layers significantly enhanced precorneal retention
and size. The phospholipids used in lipid compared to non-coated vesicles. This was only
bilayer are phosphotidylcholine, phosphotidic observed in preparations at pH 5.0 and not at pH
acid, sphingomyeline, phosphotidylserine and 7.4. Decreasing the pH of the coated vesicles
cardiolipine. The drug, depending on its solubility to 5.0 has been shown to change the initial and
characteristics, will be incorporated into either basal drainage rates such that there is significant
the aqueous compartment or the lipid layer. increase in precorneal retention. The enhanced
Thus, liposomes can entrap both hydrophilic precorneal retention may result from the binding
and lipophilic compounds, so that it is possible of polymer to the mucin. At pH 5 the adhesion is
to apply water-insoluble drugs in a liquid greater possibly due to protonation of the carboxyl
dosage form. Because of the nature of the groups, thereby permitting hydrogen-bonding
components used for their preparation, liposomes
between the polymer and the mucin layer.
are biocompatible and bioerodible vesicles.
Since the cornea has been shown to have poor
Liposomes are more suitable for lipophilic drugs
endocytic activity, other proposed mechanisms
because hydrophilic drugs tend to leak out quickly
by which liposomes interact with cells such as
from the lipid enclosure. The storage stability
lipid exchange, contact release, adsorption and
of liposomes is poor. In some cases, liposomes
fusion, may predominate. Consequently, the rate
have been shown to improve efficacy, reduce
and extent of drug release from the vesicles may
toxicity, prolong activity and provide site-specific
be an important prerequisite for drug absorption
delivery. Liposomes may not only offer a means
at precorneal sites, particularly the corneal
to reformulate established drugs but also represent
epithelium.
a novel dosage form, which can be used for new
therapeutic entities unsuitable for traditional Nanoparticles: Nanoparticles are polymeric
dosage form development.13 colloidal particles ranging in size from 10 to
Biodisposition and pharmacological studies 1000 nm. They consist of macromolecular
have demonstrated that vesicles carrying a materials, in which the drug is dissolved,
positive surface charge often outperform vesicles entrapped, encapsulated, and/or to which the drug
with a neutral or negative charge. In vitro is adsorbed or attached.They can be classified
studies have shown that binding of liposomes into two groups: nanospheres and nanocapsules.
to the cornea decreased in the order of positive, Nanospheres are small solid matricial spheres
consisting of dense solid polymeric network. stabilize the interfacial area. They have a
Drugs can either be incorporated in the matrix transparent appearance, thermodynamic stability
of the nanospheres or adsorbed onto the surface and a small droplet size in the dispersed phase
of the colloidal carrier. Nanocapsules are small (< 1.0 mm). Microemulsions are an interesting
capsules with a central cavity (oily droplet) alternative to topical ocular drug delivery,
surrounded by a polymeric membrane. Various because of their intrinsic properties and specific
polymers can be used to fabricate nanoparticles structures; they can be easily prepared through
such as polyacrylamide, polymethylmethacrylate, emulsification, can be easily sterilized, are
polylactic-co-glycolic acid and E-caprolactone. stable and have a high capacity for dissolving
All of these polymers are biodegradable and drugs. The administration of oil-in-water
undergo hydrolysis in tears. The drug polymer microemulsions could be advantageous, because
binding depends upon the physicochemical of the presence of surfactant and co-surfactant,
characteristics of both and determines the which act as penetration enhancers. Moreover,
rate of drug release. Nanoparticles are coated microemulsions achieve sustained release of a
with bioadhesive polymers like chitosan. This drug applied to the cornea and higher penetration
prolongs the stay of particles in the cul-de-sac into the deeper layers of the ocular structure
and corneal surface. Nanoparticles as drug and the aqueous humor than the native drug.
carriers for ocular delivery have been found Additional advantages of these systems include:
to be more efficient than liposomes and in low viscosity, a greater ability as drug delivery
addition to all positive features of liposomes, vehicles and increased properties as absorption
the nanoparticles are exceptionally stable and promoters. The possibility of prolonged release
the sustained release of drug can be modulated.14 of drugs in microemulsions makes these vehicles
very attractive for ocular administration and can
Niosomes: The niosomes are physically similar to
greatly decrease the frequency of application of
liposomes but the vesicle membrane is made up
eye drops. Besides this, the low surface tension
of nonionic surfactant. Niosomes are chemically
of microemulsions also guarantees a good
stable and entrap both the hydrophilic and
spreading effect on the cornea and mixing with
lipophilic drugs. Niosomes contain nonionic
the precorneal film constituents, thus possibly
surfactants, which are non-antigenic and non-
improving the contact between the drug and
toxic to the eye so they can be used over a longer
the corneal epithelium. Some of the developed
period of time.The bioavailability of hydrophilic
microemulsions also presented a viscosity value
drugs is better than liposomes as the surfactant
that allows sterile filtration and easy dispensing
also acts as penetration enhancer. Niosomes
as eye drops.
provide site-specific drug delivery for prolonged
period and are stable on storage.15
Other Drug Delivery Systems
Discomes: The discomes are similar to niosomes
but the particle size is larger (12–16 µm). Solulan Cyclodextrins
C24 is the nonionic surfactant used. They are
The pharmaceutical use of cyclodextrins (CD)
retained in the cul-de-sac and are poorly drained
is confined mainly to the complexation of
into the systemic circulation due to large particle
problematic drugs (poorly soluble, unstable,
size. They provide prolonged drug release of
irritating, and difficult to formulate substances).
hydrophilic drugs.16
CD complexation generally results in improved
M i c r o e m u l s i o n s : M i c r o e m u l s i o n s a r e wettability, dissolution, solubility, stability
dispersions of water and oil that require surf and reduced side-effects.17 CDs are a group
actant and co-surfactant agents in order to of homologous cyclic oligosaccharides with a
hydrophilic outer surface consisting of six, seven tear fluid, swells and is converted to a gelatinous
or eight glucose units. Although soluble in water, mass. This gelatinous mass keeps on releasing
CDs have a lipophilic cavity in the center. They the polymer over 24 hours. Lacrisert is useful
form inclusion complexes with many lipophilic in the treatment of moderate to severe dry eyes.
drugs by taking up a drug molecule, or part of Some amount of basal tear secretion is necessary
it, within the lumen, resulting in an increase for lacrisert to act and in eyes with absolute tear
in solubility. The first cyclodextrins studied, deficiency lacrisert fails to provide therapeutic
had relatively low aqueous solubility and were benefit. Although, once a day application provides
shown to cause hemolysis and nephrotoxicity, sufficient relief of symptoms, some patients
These cyclodextrins had only limited use. Among may require twice a day insertion. Lacrisert is
cyclodextrin derivatives, hydroxypropyl-fl-cyclo generally well tolerated and displacement of
dextrin has been shown to be the most favorable the device is uncommon. The most common
in the hemolysis study on human erythrocytes. problems encountered during its use are foreign
body sensation and blurred vision due to spread
Inserts of polymer over cornea.
A collagen shield is a soluble insert, which
Inserts can be erodible or non-erodible. They have offers the advantage of being entirely soluble so
proven long duration of release and ability to that it does not need to be removed from its site
modify drug bioavailability when compared with of application, thus limiting the interventions to
their solution dosage forms. Although, inserts insertion only. Collagen shields are made up of
have shown therapeutic success, they are not well porcine or bovine scleral collagen. They are thin
tolerated by patients, and considering their high membranes ranging in diameter from 14.5–16
cost per dose, are not perceived as desirable next- mm. The water content varies from 63–85%.
generation topical ocular drug delivery systems.18 They are packaged as dehydrated shields. Before
Ocusert® (Alza Corporation) is an insoluble insertion they are soaked for about 3 minutes in
ophthalmic insert classified in the group of saline, lubricant or drug solution. The rehydrated
diffusional systems. It consists of a central shield upon insertion takes the shape of cornea.
reservoir of drug (e.g. pilocarpine) enclosed Initial insertion may be uncomfortable and may
between two semipermeable membranes, which require use of a local anesthetic. Following
allow the drug to diffuse from the reservoir at a
insertion, collagen shields undergo dissolution by
precise rate for a period of 7 days. Prolonged
the enzymes in tear film and release the drug on
reduction in intraocular pressure was achieved
ocular surface. Dissolution time depends upon the
with a single Ocusert® in patients with open-angle
amount of cross-linking in its material and varies
glaucoma. Because of the insolubility of the
from 12–72 hours for different preparations.
Ocusert® device, it must be removed after use.
The oxygen permeability of collagen shields is
The inserts were well tolerated but after prolonged
comparable to that of hydroxyethyl methacrylate
wear they tend to swell and partially fragment.
lens of similar water content.
Now it is recommended that they not be worn
for more than 12 hours, despite the potential for For conditions requiring prolonged drug
prolonged release over several days. delivery to ocular surface collagen shields are more
Lacrisert is a solid artificial tear preparation effective, convenient and safe devices as compared
measuring about 1 mm in width, 4 mm length to multiple daily eye drops, daily subconjunctival
and contains 5 mg of hydroxypropyl cellulose injections or soft contact lenses. However, collagen
without preservative. It is packaged in dehydrated shields are expensive and are available in a limited
form and with the help of an applicator is inserted number of base curves and diameters, which may
into the inferior fornix. After insertion it imbibes not be suitable to fit on all corneas. They can
cause foreign body sensation and allergy. Using the cornea, non-irritant, and able to release the
collagen shields to deliver a combination of drugs parent drug within the eye at a rate that meets
may be problematic due to drug-drug interactions. therapeutic need.
They should be used with caution in patients with
compromised corneal endothelium and cases of POSTERIOR SEGMENT DRUG
significant chemical burn.
DELIVERY SYSTEMS
Prodrug (Chemical Delivery System) Iontophoretic Devices
Use of prodrug molecules of some drugs allows Numerous iontophoretic devices with different
better corneal drug permeation. It also gives capabilities are commercially available. The most
selective and site-specific drug delivery. Some basic of these units consist of two electrodes, a
of the drugs used in prodrug forms include power source, timers, and an ampere meter for
epinephrine, phenylephrine, albuterol. Soft- measuring current output. As iontophoresis is not
drugs, unlike prodrugs, are active drugs, which entirely without risks, efforts are continuously
are designed to undergo a predictable and made to develop systems that can substantially
controllable deactivation in vivo. An example of reduce, if not eliminate, any risk of injury caused
ophthalmic application of the soft-drug approach by use of the device. The systems discussed
is metoprolol. If the prodrug approach is applied to below represent a small sampling of those
a soft-drug the resulting drug is known as a ‘pro- available.
soft drug’. A chemical delivery system (CDS) or
site-specific CDS is an inactive drug derivative,
Coulomb Controlled Iontophoresis (CCI)
which undergoes several predictable enzymatic
transformations via inactive intermediates The amount of drug delivered by iontophoresis
and finally delivers the active drug to the site depends on the current density, duration of
of action. Ophthalmic applications of a CDS treatment, drug concentration, pH, and the
include adrenolone esters (CDS of adrenaline), permeability of the tissue for the drug molecule.
propanoloneoxime (CDS of propanolol) and As current is being applied, the damage to tissues
alprenoxime (CDS of alprenolol). caused by heat may affect the hydration level of
Prodrugs were introduced in ophthalmology the tissue. With time, the resistance may change in
about 30 years ago when ocular absorption the damaged tissue, resulting in variable electrical
of epinephrine was substantially improved fields. Thus, the iontophoretic character of the
by its prodrug, dipivefrine. Currently, it has drug being applied changes with time. The CCI
replaced epinephrine in the treatment of elevated system was developed to avoid these problems.20
intraocular pressure associated with glaucoma. The CCI iontophoretic system produces and
Since dipivefrine, numerous prodrugs have been maintains a constant electrical field across the
designed to improve the efficacy of ophthalmic conjunctival epithelium, allowing a constant drug
drugs, to prolong their duration of action and/ flow (i.e. electrical current) during transscleral
or to reduce the systemic side-effects. Prodrugs iontophoresis. The ability of the CCI system to
have been tested experimentally and clinically automatically adjust to changes in resistance is a
but stability and solubility problems as well as major advantage over other iontophoretic delivery
local irritation after topical application have methods. Poor probe contact or disruption of the
limited their efficacy and clinical acceptability.19 circuit is indicated by an audio-visual alarm, and
An ideal ocular prodrug should be stable and the instrument continuously records the total
soluble in aqueous solutions to enable formulation, Coulombs delivered, thus ensuring a calibrated
sufficiently lipophilic in order to penetrate through and controlled delivery of drug.
Mini-ion Iontophoretic Unit the human sclera by an electrical field.23 The

sclera has many microscopic to molecular-scale,
The mini-ion device is portable and can be water-filled pores. The pores in the sclera are large
operated by battery or external electrical source. enough for nucleic acids to wander through under
The mini-ion device applies a variable electrical the influence of an electrical field.
current in the range of 0.1–1.0 mA for preset
periods of 10–120 s. The device uses a disposable
drug-loaded hydrogel probe to safely deliver
Scleral Implants
doses of charged drugs to different segments of Sustained release scleral implants provide
the eye following transscleral iontophoresis.21 controlled drug release that is achieved by a
polyvinyl alcohol membrane.It has been observed
Eyegate that in terms of the drug release profile, an implant
with a non-biodegradable polymer membrane is
The Eyegate iontophoresis device/applicator is more controllable than one using a biodegradable
made of medical grade, soft silicone rubber and is polymer. Since non-biodegradable devices could
designed to closely fit the human eye contour and release drugs over a longer period of time, these
palpebral conjunctival opening. The applicator has systems may be well suited for the treatment of
an annular shape; the diameter of the proximal part chronic ocular diseases, such as age-related macular
is slightly larger than the limbus, while the distal degeneration and diabetic retinopathy.24 This
part covers 2 mm of the anterior sclera behind the system may be more useful than the intravitreal
limbus. The annular well of the device (0.5 cm3) drug delivery systems in delivering the drug more
contains a pure tungsten electrode immersed in the effectively to the macular region without increasing
solution.22 The drug solution is infused into the drug concentration in the aqueous humor and site-
applicator via two silicone tubes, one of which is specific treatment in the retina-choroid.
a drainage tube that generates a slight suction to
maintain the applicator in perfect contact with the
conjunctiva and ensures a constant flow of drug
Transdermal Systems
inside the cup. Vanes located between the walls Transdermal therapeutic systems (TTS) enable
prevent the electrode from touching the eye, but one to avoid the peaks and valleys in the drug
allow drug contact with the conjunctiva and sclera plasma levels that occur with oral dosing. Large
(fluidic surface of 0.5 cm2). The drug solution does variations in the plasma levels of any drug
not cover the corneal surface and vision is not may cause unwanted side-effects. A new TTS
impaired during treatment, which makes treatment for delivery of ocular drugs has been reported
more comfortable for the patient. for prednisolone.25 The results suggested that
the prednisolone-TTS was more effective than
Electrical Fields conventional topical or oral administration.
Furthermore, the ocular bioavailability and tissue
The basis of electrophoresis, electroporation, concentration profiles suggest that other ocular
or iontophoresis is the use of an electrical field hydrophobic drugs similar to prednisolone may be
to enhance delivery of substances into and/or amenable to TTS delivery. Thus, TTS delivery of
across support media, cell membranes or tissues. ocular drugs may be a safe and effective method
The DNA and RNA, being hydrophilic and for treating chronic posterior segment diseases.
highly charged at neutral pH, would be ideal
molecules for enhanced ocular drug delivery by
Photodynamic Therapy
electrical fields. It has been demonstrated that
small RNA or DNA (up to 8 million Daltons) Photodynamic therapy plays an important role
synthetic oligonucleotides could be driven across in the treatment of neovascular age-related
macular degeneration. The method requires Extraocular Irrigation
intravenous administration of a photosensitive
dye, verteporfin. The dye accumulates in the Extraocular irrigation with copious amount
neovascular tissue and is activated by exposure of fluid is required in the treatment of acute
to non-thermal light at 689 nm. This activation chemical burns, to remove foreign body, dye or
generates free radicals, which cause cell death and viscous fluid used in gonioscopy. With patient in
occlusion of abnormal new vessels. The method supine position and head tilted towards the side
helps in destroying the neovascular tissue with to be irrigated, extraocular irrigation fluid at room
minimal or no damage to normal vasculature. temperature is delivered to the surface of eye from
a simple container. The fluid flowing out of the
eye is removed or collected in tissue, towel or
MODES OF ADMINISTRATION a collecting pan. The method is easy to use and
OF TOPICAL OPHTHALMIC cost-effective but requires an attendant to carry
FORMULATIONS out the irrigation. For patients who require long-
term irrigation and especially those who are not
The most common route of drug administration ambulatory, continuous irrigating system is used.
in ophthalmology is by topical application and, This irrigation system consists of a polyethylene
therefore, several modes of topical application tube, which is inserted through the lid and is placed
are in use. Instillation of liquid ophthalmic in lower fornix. The other end of tube is anchored
formulations is the most commonly employed to the skin by stitches or tapes and connected with
method. The method of topical instillation an overhead reservoir, from which fluid flows into
is described in Chapter 2. The modes of the eye. The flow can be controlled with the help
topical administration other than instillation are of an adaptor attached to tubing. The system is
described here. usually well tolerated with no apparent discomfort.
In cases where lid penetration by tubing is not
Sprays desirable, other measures such as loops, rings,
tubes and heptic contact lens shells are used.
Sprays are the alternative method of delivering
ophthalmic solutions to eye. They are less
Lid Scrubs
irritating than solutions. The spray device is
held at a distance of 5–10 cm from eye and the Lid scrubs consist of solutions and ointments
lid margins of gently closed eyes are sprayed. applied directly to lid margins with the help of
Subsequently, patient is asked to blink several a cotton-tipped applicator. Baby shampoo or
times over 10–15 seconds. A stinging sensation is other eyelid cleansers are used to clean the lid
an indicator of the presence of drug in precorneal margins in contact lens users or to remove oil,
tear film. If no stinging sensation is experienced debris and desquamated skin in inflamed eye.
a second application is required. Use of lid scrubs is especially helpful is cases of
Mydriatic and cycloplegic combinations such blephritis and the efficacy is better as compared
as phenylephrine-tropicamide or phenylephrine- to instillation of drops or ointment in the inferior
fornix. Antibiotics can also be used as scrubs. The
tropicamide-cyclopentolate can be used in the
commercial preparations available as lid scrubs
form of spray. Their efficacy is as good as that of
should not be instilled directly into the eye.
solutions and risk of contamination is negligible.
Application with eyes closed allows only minimum
quantity to reach the precorneal tear film. Ocular Filter Paper Strips
irritation is less and patient acceptability is high Ophthalmic dyes such as fluorescein sodium,
especially with pediatric patients. rose bengal and lissamine green are available
as drug-impregnated filter paper strips. The of drug are complementary to each other, better
strips are moistened with a drop of saline or drug permeation occurs. Lenses with high water
extraocular irrigating solution and are touched content absorb higher amounts of water soluble
with the superior or inferior bulbar conjunctiva drugs. Thicker lenses absorb and store greater
or inferior fornix. The method allows easy amount of drug whereas thinner lenses allow
administration of adequate amount of drug. greater amount of drug to enter precorneal tear
Administration of excessive quantity of drug film. Higher concentration of soaking solution
is avoided. Importantly, the methods helps in and longer soaking time allows greater drug
avoiding contamination due to use of solution permeation into the lens. The efficacy of soft
especially the risk of contamination of sodium contact lenses as drug delivery devices has
fluorescein with Pseudomonas aeruginosa is been found to be as good as subconjunctival
eliminated. Separate filter paper strips should be injections. Use of hydrogel contact lenses
used for two eyes to avoid cross-contamination. in conjunction with ophthalmic solutions
containing benzalkonium chloride has also been
Cotton Pledgets found to be clinically acceptable.
Cotton pledgets are thin and elongated cotton

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(4-5):130–2. controlled iontophoresis of methylprednisolone
11. Gurny R, Ibrahim H, Aebi A, Buri P, Wilson CG, into the rabbit eye: influence of duration of treat-
Washington N, et al. Design and evaluation of ment, current Intensity and drug concentration
controlled release systems for the eye. J Contr Rel. on ocular tissue and fluid levels, Exp Eye Res.
1985;2:353–61. 2002;74:51–9.
12. Gurny R, Boye T, Ibrahim H. ocular therapy
21. Eljarrat-Binstock E, Raiskup F, Frucht-Pery J,
with nanoparticulate systems for controlled drug
delivery. J Contr Rel. 1987;6:367–73. Domb AJ. Hydrogel probe for iontophoresis
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14. Zimmer A, Kreuter J. Microspheres and nanopar- 22. Halhal M, Renard G, Courtois Y, Ben Ezra D,
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Deliv Rev. 1995;16:61–73. bed side, Exp Eye Res. 2004;78:751–7.
15. Mahale NB, Thakkar PD, Mali RG, Walunj 23. Ambati J, Gragoudas ES, Miller JW, You TT,
DR, Chaudhari SR. Niosomes: Novel sustained
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ery of bioactive protein to the choroid and retina,
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16. Vyas SP. Discoidal niosome based controlled 24. Yasukawa T, Ogura Y, Tabata Y, Kimura H,
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ChapteR 6
Mydriatics and Cycloplegics
OVERVIEW of accommodation and stimulation of tear

secretion.
Mydriatics and cycloplegic drugs, both dilate Cholinergic receptors in sphincter and ciliary
the pupil (mydriasis). Additionally, cycloplegics muscle are of muscarinic type with predominance
paralyze the ciliary muscle and cause loss of of M 3 subtype. 3 Sympathetic input to eye is
accommodation (cycloplegia), i.e. inability to focus relatively small as compared to parasympathetic
on the near objects. Mydriatics and cycloplegics input and maintains a persistent tone in dilator
are widely used drugs in ophthalmology for muscle, aiding relaxation of the sphincter and
diagnostic and therapeutic purposes. pupillary dilatation. The time course of the
sympathetic responses is slower as compared to
parasympathetic responses and takes about 30–40
MECHANISM OF ACTION seconds to reach the peak effect. Parasympathetic
responses reach the peak effect within 1–2
The diameter of pupil is controlled by two sets of seconds.
muscles: dilator pupillae and sphincter pupillae. Sympathomimetic drugs cause contraction of
The dilator pupillae consists of radial fibers and radial fibers of dilator pupillae and, thereby, cause
is innervated by sympathetic nervous system. mydriasis. Sympathomimetic drugs have little
The adrenergic receptors in the dilator pupillae effect on accommodation and light reflex remains
are mainly α and a few β (β2-receptor subtype). intact. Sympathomimetics also affect the width
Sympathetic control of ciliary muscle action is not of palpebral fissure, diameter of ocular blood
well established. However, there is some evidence vessels and aqueous flow. Cholinergic antagonists
that sympathetic stimulation of ciliary muscle act by blocking the muscarinic receptors, which
antagonizes accommodation in human eye.1-2 are present on both the sphincter pupillae and
Sphincter pupillae consists of circular ciliary muscle, thereby, producing pupillary
fibers and is innervated by parasympathetic dilatation and paralysis of accommodation.
(cholinergic) nerves. Parasympathetic nerves Sympathomimetics are comparatively weak
also innervate ciliary body and lacrimal glands. mydriatic agents and in people with an iris difficult
Therefore, parasympathetic activation causes to dilate, such as diabetics or blacks, stronger
not only the contraction of sphincter muscle antimuscarinic agents are used. Mydriatics can
leading to pupillary constriction but also causes raise the intraocular pressure and can precipitate
ciliary muscle contraction leading to spasm glaucoma in predisposed individuals.
USES: DIAGNOSTIC AND Table 6.1 Indications for the use of mydriatics for
diagnostic purposes
THERAPEUTIC
1. Sudden decrease in visual acuity
Mydriatics and cycloplegic drugs are primarily 2. Unexplained loss of visual field
used to 3. Diabetes mellitus
1. Facilitate ophthalmoscopic examination of the
4. Symptoms of floaters, photopsia,
lens periphery, vitreous and retina. metamorphopsia, spots, shadows
2. Paralyze the ciliary muscle in young patients
5. Ocular pain in the absence of elevated
as an aid for refraction. intraocular pressure (IOP)
3. Dilate the pupil and paralyze the ciliary
6. Red eye that can not be attributed to infection,
muscle in uveitis; to prevent formation of allergy of elevated IOP
synechia and relieve the symptoms of pain 7. Recent blunt ocular trauma (except when
and photophobia. hyphema is present)
When used for diagnostic purpose, mydriatics 8. Myopia > 6D or when degenerative changes
allow examination of small details, which are present
are of great diagnostic importance such as 9. Media opacities making posterior segment
diabetic microaneurysms, hypertensive arteriolar examination difficult
attenuation, small retinal holes and other peripheral 10. Retinal diseases, detachment, tears
lenticular and retinal lesions. A reasonably good
11. Vitreous hemorrhage
examination of optic disc and retinal vessels
can be performed through an undilated pupil 12. Peripheral lenticular opacities
especially in young adults with spontaneously
large pupils but in elderly patients dilatation is Table 6.2 Contraindications for the use of mydriatics
frequently required. Moreover, the risk of missing
an important diagnostic finding by failing to dilate 1. A known or suspected case of angle closure
glaucoma
is more than the risk of precipitating glaucoma
by dilating the pupil. Therefore, it is important to 2. Abnormally narrow anterior chamber angle
perform mydriasis in appropriate cases and it is a 3. Active corneal disease
moral and legal duty of the optometrists to refer 4. Iris fixation lens pseudophakia
the pathological conditions for medical attention. 5. Hyphema
Some of the indications and contraindications for 6. Suspected penetrating ocular injury
the use of mydriatics are listed in Table 6.1 and 6.2. 7. Conditions when pupil reactions need to
be preserved such as head injury, recent
neurological anomalies, iris trauma
COMMONLY USED MYDRIATICS AND 8. Known hypersensitivity to a mydriatic drug
CYCLOPLEGICS
The mydriatics and cycloplegics commonly used
in clinical practice are: It causes contraction of dilator pupillae causing
pupillary dilatation, constriction of conjunctival
1. S y m p a t h o m i m e t i c s : P h e n y l e p h r i n e ,
hydroxyamphetamine. vessels causing blanching and contraction of
2. Antimuscarinic: Atropine, homatropine, Muller’s muscle causing widening of palpebral
hyoscine, cyclopentolate, tropicamide. aperture. 4,5 The effect of phenylephrine on
accommodation is relatively weak . It is available
in single-use units in concentrations of 2.5 and
Phenylephrine
10%. As a mydriatic agent, higher efficacy of
Phenylephrine is an α-adrenergic agonist and is the 10% phenylephrine as compared to 2.5% is
only sympathomimetic mydriatic in clinical use. not established. However, higher concentration
mydriatics and cycloplegics 89
is more often associated with adverse effects.Ocular adverse effects: Local adverse effects
of phenylephrine include stinging, pain,
Following topical application, mydriasis begins
in about 10 minutes and reaches peak in 45–60 lacrimation and keratitis. Phenylephrine can
cause allergic dermatoconjunctivitis giving
minutes. The pupil returns to pre-instillation size
a scalded appearance around the eye. It can
in 6–7 hours. These times can vary significantly.
Diabetics dilate slowly and less widely as cause transient corneal edema. In elderly
compared to non-diabetics. Phenylephrine patients, phenylephrine causes rebound miosis
10% has shown significantly higher efficacy asand re-instillation at this time gives a slow
compared to 2.5% concentration in diabetics. response. Long-term repeated use results in
slow and less intense mydriasis. In elderly
People with dark iris tend to develop mydriasis
slowly but for a longer duration as the drug patients, phenylephrine has been shown to cause
release of pigment from iris, which appears as
binds to pigment in iris. It produces less effect
on accommodation as compared to muscarinic aqueous floater in about 30–40 minutes and
antagonists. disappears in 12–24 hours.8 Long-term use of
low concentrations as ocular decongestants also
In addition to its uses as mydriatic agent,
causes rebound conjunctival congestion.
phenylephrine is also used for other therapeutic
purposes. Phenylephrine causes blanching of Skin pallor due to cutaneous vasoconstriction
caused by over spilling phenylephrine 2.5%
superficial conjunctival blood vessels (whitening
of the eye) and in very low concentrations eye drops was reported in premature neonates.9
(0.125%), it is used as ocular decongestant. Blepharoconjunctivitis and dermatitis due to
In a concentration of 10% phenylephrine is phenylephrine eyedrops has also been reported.10
applied topically for breaking synechiae. 4 Systemic adverse effects: Phenylephrine 10%
has been shown to cause rise in mean arterial
Topical 10% solution is also used for peripheral
corneal vasoconstriction during LASIK blood pressure in dogs. 11 Elderly patients
surgery. Phenylephrine 2.5% in combination especially those with cardiovascular disease
with ecothiophate can be used to prevent the are prone to develop acute rise in blood
formation of miotic cysts in the treatment pressure following topical application of 10%
of open-angle glaucoma or accommodative phenylephrine.12 Neonates and insulin-dependent
diabetics with vascular disease and autonomic
estropia.6 The mechanism involved in prevention
of cyst formation is not known. Phenylephrine dysfunction also respond similarly to 10%
also causes widening of palpebral fissure by phenylephrine. 13,14 Other systemic adverse
stimulation of Mueller’s muscle and ptosis effects of 10% phenylephrine include occipital
resulting from sympathetic denervation such asheadache, ventricular arrhythmias, tachycardia,
in Horner’s syndrome may respond favorably. reflex bradycardia, subarachnoid hemorrhage,
Phenylephrine 1% is also used in the diagnosisruptured aneurysm, skin blanching.
of Horner ’s syndrome. 7 It causes marked Cardiovascular adverse effects of topical
10% phenylephrine can be potentiated in
pupillary dilatation in the eye with postganglionic
sympathetic denervation but minimal or no patients receiving tricyclic antidepressants and
monoamine oxidase inhibitors. Patients on
dilatation in normal eye. If the lesion is central
reserpine, methyldopa and guanethidine also show
or preganglionic, the pupil behaves in the same
way as in the normal eye. excessive pressor response to phenylephrine due to
denervation hypersensitivity. Phenylephrine 2.5%
is rarely associated with systemic adverse effects
Adverse Effects
and is recommended for routine clinical use. The
Topical use of phenylephrine may give rise to guidelines for the use of 10% phenylephrine are
local as well as systemic adverse effects. outlined in Table 6.3.12,14,15
Table 6.3 Guidelines for the use of 10% phenylephrine Adverse Effects
1. Use with caution in patients with cardiac disease, Topical use of hydroxyamphetamine for routine
hypertension, insulin-dependent diabetes mellitus, mydriasis causes little, if any, ocular irritation.
aneurysm, advanced atherosclerosis, idiopathic
orthostatic hypotension Due to its indirect action it is considered
a safer mydriatic in patients with shallow
2. Do not use more than one application per hour
in each eye anterior chamber.18 Systemic absorption of the
hydroxyamphetamine can cause rise in blood
3. Do not use in atropinized patients; this can
cause tachycardia and hypertension pressure, however tachyphylaxis develops for
4. Do not use in patients receiving tricyclic
this effect. It is also ineffective in patients with
antidepressants, monoamine oxidase inhibitors, postganglionic denervation. Because of these
reserpine, methyldopa and guanethidine reasons hydroxyamphetamine is safer than
5. Use only 2.5% solution in infants and elderly phenylephrine in patients with insulin-dependent
6. Prolonged irrigation/application and diabetes, idiopathic orthostatic hypotension and
subconjunctival injection is not recommended patients receiving reserpine, methyldopa and
guanethidine.
Hydroxyamphetamine Atropine
Hydroxyamphetamine is an indirect acting Atropine is a naturally occurring alkaloid obtained
sympathomimetic. It acts by stimulating the from the plant Atropa belladonna (deadly
release of norepinephrine from adrenergic nightshade). It was the first antimuscarinic used
nerve terminals. Topical instillation of 1% in medicine and is the most potent mydriatic-
solution causes pupillary dilatation and also some cycloplegic drug. It is a non-specific muscarinic
vasoconstriction. It has no significant effect on antagonist that acts by competitively inhibiting
accommodation and refractive state.16 It is used the actions of acetylcholine. It acts both centrally
only as a mydriatic agent. The time of onset of and peripherally. It is available commercially as
mydriasis and the time to reach the peak effect is sulfate derivative in 1% solution or 1% ointment
comparable to phenylephrine 2.5%.17 However, formulation.
the maximal dilatation may not be adequate Topical application results in persistent
especially in diabetics to examine peripheral mydriasis unresponsive to light and cycloplegia.
retinal abnormalities. To achieve greater pupillary Following application of single drop of 1%
dilatation, it is used in combination with a solution, mydriasis begins in about 10 minutes
muscarinic antagonist such as tropicamide 0.25%. and reaches peak in 25–30 minutes. It starts
The mydriatic effect of this combination is returning to normal size in 2 days and reaches
independent of the effect of age or color of iris. pre-instillation size by the 10th day. Cycloplegia
Hydroxyamphetamine is useful in differe begins in about 15 minutes, reaches peak in about
ntiating preganglionic or central sympathetic 100 minutes and disappears in 7–12 days.
lesions from postganglionic lesions in Horner’s Atropine allows measurement of refractive
syndrome. In patients with preganglionic or error without interference by the accommodative
central lesion hydroxyamphetamine causes power of the eye and is, therefore, used for
pupillary dilatation by stimulating release of refraction in young children. However, shorter
norepinephrine from intact postganglionic fibers. acting cycloplegics are now preferred. People
This effect is not observed if the lesion involves above 40 years of age have decreased ability to
postganglionic fibers. accommodate and often refraction can be done
mydriatics and cycloplegics 91
without cycloplegia. Ocular pain in patients with is discontinued. Treatment involves supportive
uveitis and corneal ulcer due to ciliary muscle measures such as maintaining the patent airways
spasm is relieved by atropine, which causes ciliary and symptomatic treatment such as for fever and
muscle relaxation. Some studies have shown that CNS excitation. Physostigmine is used as antidote
prolonged use of atropine may prevent or delay to quickly terminate the systemic toxicity of
the progression of myopia.19Atropine can also be atropine and is specially useful in patients with
used to provide pharmacological occlusion in the hallucinations, seizures and cardiac toxicity.
better eye for the treatment of amblyopia.20
Homatropine
Adverse Effects and Contraindications
Homatropine hydrobromide is a semi-synthetic
Topical instillation causes transient stinging. derivative of atropine. It is available commercially
Prolonged duration of mydriasis causes in a concentration of 2% and 5%. The mydriatic
photophobia and blurred vision for many days. effect appears in 10–20 minutes and reaches
In patients with narrow angle, atropine can peak in 30–40 minutes. Both the light and
precipitate an acute attack and is, therefore, accommodative reflexes are lost in 30 minutes.
contraindicated in patients with angle closure Pupil takes 1–3 days to recover to normal size. It
glaucoma. Topical atropine exacerbates aqueous is a less potent antimuscarinic agent than atropine
tear deficiency and is, therefore, contraindicated and thus produces significantly less cycloplegia
in patients with dry eyes. It is also contraindicated as compared to comparable doses of atropine
in patients with previous history of allergy. and cyclopentolate. The duration of cycloplegia
The pharmacological response to atropine produced by homatropine is longer than that
may be potentiated if administered to patients produced by cyclopentolate, especially in people
on drugs with antimuscarinic action such as with pigmented iris.21
antihistaminics, tricyclic antidepressants and Homatropine is primarily indicated for
monoamine oxidase inhibitors. therapeutic use in the treatment of anterior uveitis as
Atropine if absorbed systemically in significant its effects are similar to atropine. It is not a preferred
amount can cause drug for fundus examination or cycloplegic
Tachycardia, headache, flushing refraction because of its prolonged duration of
Dry mouth, heartburn action and relatively weak cycloplegic action.
Exacerbation of gut hypomotility, urinary The adverse effects and contraindications of
retention in patients with enlarged prostate homatropine are same as those of atropine.
CNS toxicity in elderly patients.
Atropine should be used with caution in pediatric Scopolamine (Hyoscine)

and elderly patients. It should be used in pregnant
The alkaloid scopolamine is obtained from the
and lactating mothers only if clearly indicated.
Measures should be taken to avoid excessive shrub Hyoscyamus niger and Scopolia carnfolica.
systemic absorption such as digital pressure for It is a non-selective antimuscarinic agent and has
2–3 minutes after topical administration. effects similar to atropine, although, the duration
Systemic atropine toxicity presents with dry of mydriatic and cycloplegic action is shorter.
and flushed skin, fever, blurred vision, rapid and The maximal mydriatic effect of scopolamine
irregular pulse, distended abdomen in infants, hydrobromide 0.5% solution appears in 20–30
mental aberrations and loss of neuromuscular minutes and pupil recovers to normal size in 1–3
coordination. Atropine poisoning is usually self- days. Cycloplegia appears in 30–60 minutes and
limiting and is rarely fatal if further administration persists for 3–7 days.22
Scopolamine even in low doses easily crosses recovery occurs in 12 hours. The light reflex
blood brain barrier and produces CNS effects such is also lost so the pupils do not constrict on
as drowsiness and confusions. A high incidence of exposure to bright light such as during binocular
idiosyncratic reactions with scopolamine has been indirect ophthalmoscopic examination or fundus
reported as compared to other anticholinergic photography. In patients who are sensitive to
drugs. Therefore, scopolamine is not a preferred atropine, cyclopentolate is used for the treatment
drug for fundoscopy, cycloplegic refraction or of anterior uveitis. However, if the inflammation
treatment of anterior uveitis. Its use is reserved is severe, more frequent instillation is required
for patients showing allergy to atropine. due to its short duration of action.
The adverse effects and contraindications
of scopolamine are same as those of atropine; Adverse Effects and Contraindications
however, CNS toxicity is more common.
Contraindications for scopolamine are same as The most common adverse effect of cyclopentolate
for atropine. is stinging, burning and tearing on initial
instillation. This effect is minimum at 0.5%
concentration but increases as the concentration
Cyclopentolate increases. In patients allergic to cyclopentolate,
Cyclopentolate is a water soluble ester and is ocular irritation, redness, facial rash, lacrimation,
available commercially in concentrations of 0.5, 1 white mucus discharge and blurred vision may
and 2% solutions. Instillation of two drops of 0.5% appear within minutes or hours. Repeated use of
solution 5 minutes apart or one drop of 1% solution high concentration solutions of cyclopentolate
causes mydriasis in 20–30 minutes and cycloplegia over prolonged period causes diffuse epithelial
in 30–40 minutes. Thus the onset of mydriasis punctuate keratitis with marked conjunctival
and cycloplegia requires almost the same time but hyperemia. Cyclopentolate can increase the
the time course of the two effects is not similar. intraocular pressure in patients with primary
Pupillary dilatation lags behind the cycloplegia. open-angle glaucoma and can precipitate an attack
Adequate cycloplegia appears even before the pupil of acute glaucoma in patients with narrow angle.
is fully dilated and refraction can be done early. Systemic absorption of cyclopentolate causes
It is a less effective mydriatic in blacks and adverse effects similar to atropine but the CNS
in people with black iris. In people with light effects are more common with cyclopentolate
iris, acceptable level of cycloplegia may appear as compared to atropine. CNS toxicity of
within 10 minutes of instillation of 1% solution. cyclopentolate is manifested as drowsiness,
In blacks and people with dark iris it may take up ataxia, disorientation, slurred speech, restlessness,
to 40 minutes for acceptable level of cycloplegia tactile and visual hallucinations. The CNS
to appear. The cycloplegic effect lasts longer in symptoms are particularly common in children
blacks and in people with black iris as compared when higher concentrations (2% or multiple
to people with light iris but in all eyes cycloplegia instillations of 1%) are used. CNS symptoms
terminates within 24 hours. usually subside within 2 hours in adults and 4–6
Cyclopentolate is the cycloplegic agent of hours in children without any permanent damage.
choice for routine cycloplegic refraction in A few cases of serious toxicity with epileptic
all age groups especially in infants and young seizures have been reported especially in children
children. The cycloplegia obtained is superior with neurological impairment.23,24 As the infants
to homatropine and parallels atropine. The onset and children especially those with neurological
of cycloplegia is faster and of shorter duration. impairment are more susceptible to adverse
Although complete recovery from cycloplegia effects of cyclopentolate, it should not be used
takes about 24 hours, an acceptable level of in concentrations higher than 0.5% in this group

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54 Textbook on Clinical Ocular Pharmacology and Therapeutics

Figure 4.6 Transmembrane signaling by tyrosine kinase linked receptors

5-diphosphate (PIP2), a phospholipid component causing membrane hyperpolarization and reduced

Figure 4.7 Regulation of DNA transcription by steroids through

Modified Receptor Actions number of receptors respond excessively to

Figure 4.8 Graded dose-response curve

Figure 4.9 Potency and efficacy

Figure 4.10 Quantal dose response curve

Overview Table 5.1 Function of excipients

Table 5.2 Classification of preservatives used in ophthalmic formulations

Preservative group Chemical class Examples

Exicipients That Increase Corneal Table 5.3 Mucoadhesive performance of several

Table 5.4 Wetting and solubilizing agents used in ophthalmic formulations

Benzalkonium chloride Polyoxyl 50 stearate Polysorbate 80

Docusate sodium Polyoxyl 40 stearate Sorbitan monooleate

Nonoxynol 10 Polysorbate 20 Sorbitan monopalmitate

Octoxynol 9 Polysorbate 40 Sorbitan monostearate

Antioxidants Physicochemical properties of drugs, such as

Topical drug delivery systems 2. Control the release of drugs.

Figure 5.2 Constraints in topical ophthalmic drug delivery

Conventional Ophthalmic Dosage preservatives. Other excipients are added to

Table 5.5 Advantages and disadvantages of solutions and suspensions

Component Solution Suspension Ointment Gel Oral/injection Insert

* Component is included or generally included in the formulation, # Optional

Mini-ion Iontophoretic Unit the human sclera by an electrical field.23 The

Cotton pledgets are thin and elongated cotton

OVERVIEW of accommodation and stimulation of tear

Atropine should be used with caution in pediatric Scopolamine (Hyoscine)

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