FARMAKOLOGI

OKULAR
DR.SUFI DESRINI M.SC
General pharmacological
principles
The way in which the body handles drugs

PHARMACOKINETICS

The study of the absorption,

distribution,metabolism and excretion
of drugs
Pharmacokinetics

These parameters are important when

choosing an appropriate route of
administration for a particular drug and
pharmacokinetic factors can also be a cause
of inter-individual variability in therapeutic
response
Pharmacokinetics

Drugs may be administered by a variety

of routes
In most cases the oral route (enteral) is
preferred.
Alternative routes (perenteral) are
chosen if a drug is poorly absorbed
from the gut, causes gastrointestinal
irritation or if a specific local action is
required (as with ophthalmic drugs or
inhaled drugs to treat asthma).
Pharmacokinetics
For a drug to reach its target tissue it must
first be absorbed from its site of
administration
The rate of absorption is largely determined
by lipid solubility, which governs penetration
across cell membranes
Non-polar (unionised) compounds readily
penetrate cell membranes by diffusion
Most drugs are weak acids or bases, which
can exist in ionised or unionised forms.
Pharmacokinetics

Weak acid: (the ionisation reaction can be

represented by):
HA A- + H+
Weak Base :
BH+ B + H+
The uncharged species B or HA are lipid soluble and
will potentially pass through the plasma membrane.
The rate of membrane diffusion will additionally
depend on the molecular size and chemical
structure of the drug. For example, aminoglycoside
antibiotics are uncharged but contain a number of
hydrogen-bonding groups
Pharmacokinetics

The term bioavailability refers to the fraction of

the dose that proceeds unaltered from the site
of administration and becomes available at the
site of action.
Topical ophthalmic drugs, that undergo
systemic absorption across the nasal mucosa,
escape first pass metabolism. As a result,
bioavailability is high with a greater risk of
systemic adverse effects.
Pharmacokinetics

Once in the bloodstream, the drug can be

distributed to the tissues.
Distribution is frequently not uniform, due to
factors such as the physicochemical properties
of the drug, differences in blood flow between
tissues or degree of leakiness of the blood
vessels within a particular tissue, Plasma
protein binding
The elimination of drugs from the body occurs
by two processes: metabolism
(biotransformation) and excretion.
 Metabolism involves the enzymatic conversion
of the drug into another chemical entity,
whereas excretion consists of the elimination of
the unchanged drug (or its metabolites).
Drug metabolism involves two types of
chemical transformation, which are termed
phase I and phase II reactions
Phase I reactions are usually carried out by a
family of microsomal enzymes known as
cytochrome 450 (CYP)
Pharmacokinetics

Phase II processes (often termed conjungation)

involve the attachment of a substituent group
e.g. glucuronyl, acetyl, methyl or sulphate. The
resulting conjugate is usually polar, water-
soluble and lacking in pharmacological activity
and so can be readily excreted.
Variation in drug metabolism can result from
genetic variability or alternatively enzyme
activity can be influenced by specific drugs
Pharmacodynamics

It is the biological and therapeutic

effect of the drug (mechanism of
action)
Most drugs act by binding to regulatory
macromolecules, usually
neurotransmitters or hormone
receptors or enzymes
If the drug is working at the receptor
level, it can be agonist or antagonist
If the drug is working at the enzyme
level, it can be activator or inhibitor
OCULAR PHARMACOLOGY
Pharmacokinetics

A drug can be delivered to ocular

tissue as:
Topical administration
Local injection
Systemic administration (ingestion or
perenteral injection)
 Topical administration
Topical application of drugs is the method of choice for
most eye disease
solutions or suspensions administered as eyedrops
account for the majority of ophtalmic formulations
Including the drugs that act at the surface of the eye e.g.
Antimicrobials for superficial infection and those that pass
through the cornea to reach intraocular targets e.g.
Antiglaucoma drugs
One of the main problems with a topical route of delivery
is the rapid and extensive precorneal drug loss
Topical administration

A single drop from a conventional dropper

bottle is 40-50 l, which overwhelms the
capacity of the conjunctival sac to contain it
and following a blink only about 10 l of the
original volume remains.
The rate of tear turnover has a major influence
on precorneal drug retention time
Radioactive suspensions instilled into human
eyes show a two-thirds reduction in
radioactivity within two minutes, followed by
complete elimination after 15 minutes.
Topical administration

The loss of an instilled drug from the precorneal

area is the net result of nasolacrimal drainage, tear
turnover, binding to tear proteins and extracorneal
uptake (table 1)
Drainage of a drug through the nasolacrimal duct is
more rapid than its rate of absorption across the
cornea.
Higher rates of drainage are found with larger drop
sizes (see figure 1)
For most drugs, increasing the drop size above 20
l does not significantly increase bioavailability and
could potentially increase the risk of systemic
toxicity (figure 2)
Topical administration

Furthermore, if a drop of one medication is

followed rapidly by a drop of another, a
substantial washout occurs with a lessening of
its effect. However, after an interval of five
minutes almost no washout occurs.
Reducing the loss of the instilled drug from the
precorneal area represents a key strategy for
improved bioavailability, and various
techniques have been proposed to improve the
pre-corneal drug retention time e.g. adding
polymers such as polyvinyl alcohol or
methylcellulose to increase viscosity.
Topical administration

The cornea represents the major route for drug

entry into the anterior chamber.
Anatomically, the cornea consists of five tissue
layers: epithelium, Bowman's membrane, stroma,
Descemet's membrane and endothelium
In terms of drug penetration, only the epithelium,
stroma and endothelium represent significant
permeability barriers
The epithelium is the primary penetrant barrier,
and therefore drug lipophilicity is one of the most
important determinants of drug permeability.
Topical administration

Stroma: the hydrophilic nature it can become rate

limiting for highly lipophilic compounds
Many ophthalmic preparations are weak acids or bases,
which exist in both, unionised and ionised forms.
a weak base its unionised form (R3N) the drug can
readily cross the epitheliumconversion to its ionised
formit can be transported through the stroma
The endothelium is made up of a single layer of
squamous cells and is therefore a low resistance
barrierit favours lipophilic compoundshydrophilic
agents can cross the endothelium by a paracellular
route.
Topical administration

The rate at which a drug is absorbed is affected

by ocular disease. Infection, inflammation and
trauma can significantly alter pharmacokinetics
by increasing corneal permeability or
breakdown of blood-tissue barriers
Pre-corneal factors influencing
ophthalmic drug bioavailability

Table 1: Pre-corneal pharmacokinetics

Volume of drug instilled

Drug formulation

Tear turnover

Tear protein binding

Tissue absorption
Figure 1: Graph showing the relationship beetwen the drainage rate
of an instilled solution as an function of time for two drop sizes
Figure 2: the relationship between drop size and biovailability based on reduction in
Pupil size with 0,5% pilocarpine
Factors influencing local drug
penetration into ocular tissue

Drug concentration and solubility: the

higher the concentration the better the
penetration e.g pilocarpine 1-4% but limited
by reflex tearing
Viscosity: addition of methylcellulose and
polyvinyl alcohol increases drug penetration
by increasing the contact time with the
cornea and altering corneal epithelium
Lipid solubility: because of the lipid rich
environment of the epithelial cell
membranes, the higher lipid solubility the
more the penetration
Drug metabolism and
excretion-Topical adm
Several enzymes that are involved in drug metabolism
have been identified within the eye
These include: esterases, peptidases, ketone
reductase, monoamine oxidase, N-acetyltransferase,
oxidoreductase, and catechol-O-methyltransferase.
Some drugs are broken down by the tissues during
intra-ocular penetration, which may limit their
effectiveness. However, these pathways can be
exploited in the development of pro-drugs, where the
breakdown product is more efficacious than the parent
compound.
For example, the anti-glaucoma drug latanoprost is
metabolised by esterases on its transit through the
cornea.
Drug metabolism and
excretion-Topical adm
Drugs are eliminated from the anterior chamber
by a combination of aqueous turnover and
absorption into the tissues of the anterior uvea.
Drug binding to the pigmented tissues of the
iris and ciliary body is an additional factor,
which can influence bioavailability and may
predispose to toxicity.
For example, the mydriatic and cycloplegic
effects of cyclopentolate and tropicamide are
slower in onset in heavily pigmented irides due
to melanin binding.
Drug metabolism and
excretion-Topical adm
Following corneal penetration, drugs are
distributed into, and then eliminated from the
aqueous humour
The aqueous is continuously secreted by the
ciliary epithelium at a rate of 2-5 l/min, and
drains by two routes: a conventional route via
the canal of Schlemm, and a non-conventional
pathway through the connective tissue of the
ciliary muscle (uveo-scleral pathway)
Eyes Drops

Contact time of eye drop medication is short

The rate of transfer from the tear fluid into
cornea is critical
Cornea ephitelium and endothelium have
intercellular tight junctions
Drug concentration
Solubility
viscosity
Solubility

To traverse the cornea, a drug must pass in turn

through :
Lipid rich environment of the epithelial cell
membran
Water rich environment of the stroma
Lipid barrier at the endothelium
Storage of Eye Drops

Correct storage is important to reduce the rate

of breakdown of the ingredients in the eye
drops
Always follow manufactures guidelines
regarding expiry date and storage once opened
e.q. Protect from light
Unopened drops should be stored in their box or
in refrigerator
 Punctual Occlusion

Systemic absorption of topical

ophthalmic drops occurs through
the nasopharyngeal mucosa
Place pressure on the punctum for
2 minutes to prevent this
Ointment

Increasing the contact time of ocular

medications
Consist of petrolatum and mineral oil
Melt at body temperature
eq Chloramphenicol
Systemic administration

Drugs may enter the bloodstream

Several factors determine the delivery of
systemic drugs into eye :
- phygsicochemical characteristics of the
drug drugs with higher lipid solubilities?, the
unbound to plasma protein drugs?
- the integrity of the blood-ocular barriers
Ocular pharmacotherapeutics
Anti inflammatory agents

Glucocorticoids
NSAIDs
Antihistamine
Histamine release blocker
Anti fibrotics
Ocular Corticosteroids

Used post operatively or for ocular inflammation

ALWAYS used under the guidance of an ophthalmologist

Usually the dose is tapered down before stopping

Suspensions: must shake bottle before using

Side effects: raised IOP, systemic effects

May cause a premature cataract

Corticosteroids

Topical
E.g. fluorometholone, remixolone,
prednisolone, dexamethasone, hydrocortisone
Mechanism: inhibition of arachidonic acid
release from phospholipids by inhibiting
phosphlipase A2
Uses: postoperatively, anterior uveitis, severe
allergic conjunctivitis, vernal
keratoconjunctivitis, prevention and
suppression of corneal graft rejection,
episcleritis, scleritis
Side effects: susceptibility to infections,
glaucoma, cataract, ptosis, mydriasis, scleral
melting, skin atrophy
Corticosteroids

Systemic:
E.g. prednisolone, cortisone
Uses:posterior uveitis, optic neuritis,
temporal arteritis with anterior ischemic
optic neuropathy
Side effects:
Local:
posterior subcapsular cataract,
glaucoma, central serous retinopathy
Systemic: suppression of pituitary-adrenal
axis, hyperglycemia, osteoporosis, peptic
ulcer, psychosis
NSAIDs

May also be very useful

in reducing
inflammation and
decreasing eye pain,
though they are usually
not as potent as
corticosteroids
NSAID

E.g. ketorolac, diclofenac, flurbiprofen

Mechanism: inactivation of cyclo-oxygenase

Uses: postoperatively, mild allergic conjunctivitis,

episcleritis, mild uveitis, cystoid macular edema,
preoperatively to prevent miosis during surgery

Side effects: stinging

Anti-allergics

Avoidance of allergens, cold compress, lubrications

Antihistamines (e.g.pheniramine, levocabastine)
Decongestants (e.g. naphazoline, phenylepherine,
tetrahydrozaline)
Mast cell stabilizers (e.g. cromolyn, lodoxamide,
pemirolast, nedocromil, olopatadine)
NSAID (e.g. ketorolac)
Steroids (e.g. fluorometholone, remixolone,
prednisolone)
Drug combinations
 Antimicrobial Agents

Used to prevent growth of bacteria introduced

into the wound by surgery or injury
Ingredients must be sterile and inert
Antimicrobial Agents

1. Ciprofloxacin HCL
2. Chloramphenicole Cendo Fenicol,
Ikamicetin, etc
3. Tobramycin
Antibiotics

Trachoma can be treated by

topical and systemic
tetracycline or erythromycin,
or systemic azithromycin.
Bacterial keratitis (bacterial
corneal ulcers) can be
treated by topical fortified
penicillins, cephalosporins,
aminoglycosides,
vancomycin, or
fluoroquinolones.
Bacterial conjunctivitis is
usually self limited but
topical erythromycin,
aminoglycosides,
fluoroquinolones, or
chloramphenicol can be used
 Antifungals
Uses: fungal keratitis, fungal endophthalmitis

Polyenes
damage cell membrane of susceptible fungi
e.g. amphotericin B, natamycin
side effect: nephrotoxicity

Imidazoles
increase fungal cell membrane permeability
e.g. miconazole, ketoconazole

Flucytocine
act by inhibiting DNA synthesis
Antivirals

Acyclovir
interact with viral
thymidine kinase
(selective)
used in herpetic keratitis
Trifluridine
more corneal penetration
can treat herpetic iritis
Ganciclovir
used intravenously for
CMV retinitis
Mydritics
Mydriatics are drugs that cause pupil
dilatation
Usually used to examine the fundus

May be used for pain relief e.q. Iritis

The most common on used is Mydriacyl
(Tropicamide)
15 minute onset, can last for 3 to 6 hours

Will blur vision

Mydriatics (cont)

other dilating drops for example:

- atropine

- Homatropine : long acting : may last 7-10

days
!! Pengunaan Midriatik pelebaran pupil
mata lbh sensitif thd cahaya kacamata
UV
Miotics

Constrict the pupil e.q. Pilocarpine

Used to treat glaucoma

Can cause :
- night blindness
-Stinging on instillation
-brow ache or spam
*long term Pilocarpine may be very difficult to
dilate
Glaucoma Medications
To reduce the eyes intraocular pressure, the fluid pressure
inside the eye, to prevent damage to the optic nerve
resulting in loss of vision
Common glaucoma medications:
Betablockers(secretion ): timolol, metilpranolol,carteolol
Prostaglandin analogues (outflow ): Latanoprost
Cholinergic agonist: pilocarpine
Alpha agonist (outflow): Brimonidine, iopidine
Carbonic anhydrase inhibitors (secretion): Dorzolamide
Adrenergic agonist: epinephrine
Ocular Topical
Anaesthetics
Temporarily block nerve conduction in the
cornea and conjunctiva, e.q. Amethocaine
0,5%, 1%
Quick onset : 10-2- seconds
Duration: 10-20 minutes
Do not use in the case of penetrating eye injury
Used to assist in the case with eye examination
and visual acuity testing: foreign bodies,
chemical burn
Ocular toxicology
Complications of topical
administration
Mechanical injury from the
bottle e.g. corneal
abrasion
Pigmentation: epinephrine-
adrenochrome
Ocular damage: e.g.
topical anesthetics,
benzylkonium
Hypersensitivity: e.g.
atropine, neomycin,
gentamicin
Systemic effect: topical
phenylephrine can
increase BP
Amiodarone

A cardiac arrhythmia drug

Causes optic neuropathy (mild decreased vision, visual field
defects, bilateral optic disc swelling)
Also causes corneal vortex keratopathy (corneal verticillata)
which is whorl-shaped pigmented deposits in the corneal
epithelium
Digitalis

A cardiac failure drug

Causes chromatopsia (objects appear yellow)
with overdose
Chloroquines

E.g. chloroquine,
hydroxychloroquine
Used in malaria,
rheumatoid arthritis, SLE
Cause vortex
keratopathy (corneal
verticillata) which is
usually asymptomatic
but can present with
glare and photophobia
Also cause retinopathy
(bulls eye maculopathy)
Chorpromazine

A psychiatric drug
Causes corneal punctate epithelial opacities,
lens surface opacities
Rarely symptomatic
Reversible with drug discontinuation
Thioridazine

A psychiatric drug
Causes a pigmentary retinopathy after high
dosage
Diphenylhydantoin

An epilepsy drug
Causes dosage-related cerebellar-vestibular
effects:
Horizontal nystagmus in lateral gaze
Diplopia, ophthalmoplegia
Vertigo, ataxia
Reversible with the discontinuation of the drug
Topiramate

A drug for epilepsy

Causes acute angle-closure glaucoma (acute
eye pain, redness, blurred vision, haloes).
Treatment of this type of acute angle-closure
glaucoma is by cycloplegia and topical steroids
(rather than iridectomy) with the
discontinuation of the drug
Ethambutol

An anti-TB drug
Causes a dose-related optic neuropathy
Usually reversible but occasionally permanent
visual damage might occur
Agents that Can Cause
Toxic Optic Neuropathy
Methanol high-protein diet
Ethylene glycol (antifreeze) Carbon monoxide
Chloramphenicol Lead
Isoniazid Mercury
Ethambutol
Thallium (alopecia, skin
Digitalis rash, severe vision loss)
Chloroquine Malnutrition with vitamin
Streptomycin B-1 deficiency
Amiodarone Pernicious anemia
Quinine (vitamin B-12
Vincristine and methotrexate
malabsorption
(chemotherapy medicines) phenomenon)
Sulfonamides Radiation (unshielded
Melatonin with Zoloft exposure to >3,000
(sertraline, Pfizer) in a rads).
HMG-CoA reductase
inhibitors (statins)
Cholesterol lowering agents
E.g. pravastatin, lovastatin, simvastatin,
fluvastatin, atorvastatin, rosuvastatin
Can cause cataract in high dosages specially if
used with erythromycin
Other agents

methanol optic atrophy and blindness

Contraceptive pills pseudotumor
cerebri (papilledema), and dryness (CL
intolerance)
Chloramphenicol and streptomycin
optic atrophy
Hypervitaminosis A yellow skin and
conjunctiva, pseudotumor cerebri
(papilledema), retinal hemorrhage.
Hypovitaminosis A night blindness
(nyctalopia), keratomalacia.
KEY POINTS TO
REMEMBER
Most ocular drugs have potential for systemic
effects
Always consider the correct storage
Do not forget to ask patient if they are presently
using eye medication, this will indicate current
ocular disease and disorders
Eye drops or ointments are never instilled in a
penetrating eye injury
Thank You