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ANTIGLAUCOMA MEDICATIONSPART I
DR PRATIBHA THILAK
PHARMACOKINETICS OF TOPICAL
DRUGS
• a) drug kinetics in the conjunctival cul-de-sac,
• (b) corneal and transconjunctival-scleral
penetration, and
• (c) the distribution and rate of drug
elimination within the eye
DRUG KINETICS IN THE CONJUNCTIVAL
CUL-DE-SAC
• first mixes with the tears in the cul-de-sac
• depends on blink movements for mixing with
instilled drugs
• 7 to 9µl of tears and has a maximum capacity
of about 30 µl
• 25.1 to 56.4 µl with an average of 39 µl
• enters the lacrimal drainage system as a result
of the pumping action created by blink
movements
• DRUG LOSS FROM TEARS
• Decreases bioavailability
• Increases systemic toxicity
• nasolacrimal occlusion
CORNEAL AND TRANSCONJUNCTIVALSCLERAL PENETRATION
• cornea as lipid-water-lipid sandwich
• selective barrier
• differential solubility concept
• drugs tend to concentrate in various layers of
the cornea
• depot and a limiting factor for transfer of the
drug to the aqueous humor
• enzymes that are important in activating some
glaucoma drugs to their active form, such as
dipivefrin and bimatoprost
INTRAOCULAR FACTORS INFLUENCING
DRUG CONCENTRATIONS
• factors affecting the bioavailability of the drug
• intraocular circulation, local tissue binding, and
local tissue metabolism
• eliminated by diffusion into the vascular system
or escapes with the aqueous via the outflow
system
• bound to various ocular tissues
FORMULATIONS OF TOPICAL DRUGS
• vehicle, pH, concentration, and additives of
the formulation
VEHICLES
• influencing the rate of drug loss in the tears, the
precorneal tear film saturation, and the length of
time that the drug remains in contact with the
cornea
• methylcellulose and polyvinyl alcohol
• increasing tear viscosity, providing solution
homogeneity (uniform suspension of drug
particles in solution), and reducing surface
tension
• Ointments significantly increase drug
bioavailability by
• reducing loss in the tears,
• inhibiting dilution by the tears,
• providing a higher effective concentration of
the drug, and
• increasing tissue contact time
• polysaccharide gum formulations
• Liposomes
• small, homogenous unilamellar structures
composed of phospholipids and water
• Temperature-sensitive liposomes, which
release substances in the ocular vasculature
when exposed to heat produced by an argon
laser or microwave
solid materials
• release a drug at a sustained rate from a
location on the cornea or in the conjunctival
cul-de-sac
•
•
•
•
water-soluble polymer matrices
insoluble material
presoaked hydrophilic contact lenses
collagen corneal shields
pH, MOLECULAR WEIGHT, AND DROP
SIZE
• A greater degree of corneal penetration
occurs when a higher concentration of
nonionized (lipid soluble) drug exists in the
instilled drop
• Weak bases absorbed through the cornea at a
higher pH, while weak acids are absorbed
better at a lower pH
• molecular weight greater than 500 g/mole
have poor corneal absorption
• CONCENTRATION
• enhanced by increasing the concentration of a
drug up to a point
• decreases with increasing concentrations, and
the greater amount of drug lost in the lacrimal
drainage system increases the potential for
systemic side effects
ADDITIVES
• benzalkonium chloride and benzododecinium
bromide
• providing bacteriostatic activity,
• decreases the surface tension of nonpolar
drugs, allowing them to mix more readily with
the precorneal tear film, leading to enhanced
corneal absorption
PHARMACOGENETICS
• Compliance
• biological mechanisms related to aqueous
humor dynamics ocular and systemic
conditions
• environmental factors and genetics
PROSTAGLANDINS AND HYPOTENSIVE
LIPIDS
• Eicosanoids
• Inactivated in lung and liver
Endogenous –PGD2,PGE2,PGF2α,PGI2,TXA2
MECHANISM OF ACTION
•
•
•
•
PROSTANOID RECEPTORS
EP,FP,IP,TP
GPCR
FP-type A,type B
• RELAXATION OF CILIARY MUSCLE
• REMODELLING OF EXTRACELLULAR MATRIX
• SHORT ONSET , LONG LASTING RELAXATION,
NARROWING OF MUSCLE FIBRE BUNDLES
•
PGF2α
FP
IP3
NFκB C-FOS
AP-1
MMP
COLLAGEN TYPE-I II IV,LAMININ,FIBRONECTIN,HYALURONS
LATANOPROST
• 0.005%.ONCE DAILY
• LOWERS IOP AT NIGHT AND DAY AS WELL
• UNIFORM ROUND THE CLOCK IOP REDUCTION
WHEN USED ALONE OR IN COMBINATION
• SAFE BUT LESS EFFECTIVE IN CHILDREN
• BETTER RESPONSE IN OLDER CHILDREN AND
JUVENILE ONSET OAG
EFFICACY STUDIES
• As effective as timolol in chronic ACG
• Effective in lowering IOP when IOP elevation
persists after peripheral iridectomy
UNOPROSTONE
• 0.15%, 0.12%
• Not as effective as timolol and latanoprost
• Increase activity of inhibitors MMP
TRAVOPROST
• 0.004%
• MORE EFFECTIVE THAN TIMOLOL IN SOME
STUDIES
• AS EFFECTIVE AS LATANOPROST
• Lowers IOP in chronic ACG
BIMATOPROST
• 0.03%
• AMIDE ETHYL GROUP AT C1 POSITION
• PROSTAMIDE
• HYDROLYZED BY CORNEA TO A LESSER EXTENT
• Fp receptor agonist + trabecular outflow+
alternative signalling pathway
EFFICACY
• Greater IOP lowering efficacy than timolol
• Similar IOP lowering effect as latanoprost
• Lower IOP in chronic ACG
ADMINISTRATION
• ONE DROP DAILY
• UNOPROSTONE-TWO DROPS DAILY
• SHORT T1/2
• IV-9.2 MINS,TOPICAL-2.3 MINS
• THERMAL AND ULTRAVIOLET INSTABILITY
• STORED UNDER REFRIGERATION
DRUG INTERACTION
• LATANOPROST 0.005% + TIMOLOL 0.5%
• TRAVOPROST 0.004% + TIMOLOL 0.5%
• ADDITIVE EFFECT WITH MIOTICS
SIDE EFFECTS
• Greater conjunctival hyperaemia than timolol
treated eyes
• Latanoprost increased number of
fibroblasts,goblet cells
• h/o herpes simplex keratitis
• Cautious use of this class of drugs is advised in
eyes with risk factors for cystoid macular
edema
• increased pigmentation in the periocular skin
and iris, and alterations in the eyelid cilia
• melanin content is increased in iris stromal
melanocytes without proliferation of cells
• mechanism of increased skin pigmentation
appears to be related to enhancing tyrosinase
activity , and altering the chemistry of the
melanin
• alterations in eyelid cilia include hypertrichosis
and increased pigmentation
• stimulating the growth phase of the hair cycle
in the dermal papilla
• Approval of bimatoprost 0.03% for treatment
of hypotrichosis of eyelashes
• allergic contact dermatitis to latanoprost ,iris
cyst associated with latanoprost and herpes
simplex dermatitis
• No significant systemic reactions
Little effect on cardiovascular and respiratory
systems
Β ADRENERGIC RECEPTOR
ANTAGONIST
MECHANISM OF ACTION
• Reducing aqueous humor production
• β2 subtype found on ciliary processes and TM
• Inhibition of c-AMP
• Outflow facility not influenced
• Does not influence blood aqueous barrier
TIMOLOL
• Timolol maleate and hemihydrate
• 0.25 %,0.5%
Non selective β1,β2 antagonist
Iop lowering effect in treated and fellow
untreated eye
EFFICACY
• Epinephrine-greater
• Pilocarpine-equivalent or slightly greater
BETOXALOL
• Cardioselective
• β1 adrenergic antagonist
• 0.25%
• Efficacy less than timolol
LEVOBUNALOL
• Non selective β1,β2 antagonist
• 0.5% ONCE DAILY
• SIMILAR IN EFFICACY TO
TIMOLOL,METIPRANOLOL
• GREATER EFFICACY THAN BETAXOLOL
CARTEOLOL
Non selective β antagonist
intrinsic sympathomimetic activity
1%, 2%
May decrease cardiovascular risks a/w
cholesterol abnormaliies
Less ocular irritation than timolo
METIPRANOLOL
• Non selective β antagonist
• 0.3%
• COMPARABLE WITH TIMOLOL AND
LEVOBUNOLOL IN EFFICACY AND SAFETY
ATENOLOL
• selective β1 antagonist
• 2%
METOPROLOL
• Cardioselective
• β1 adrenergic antagonist
• 1-5%
• EQUIVALENT EFFICACY TO TIMOLOL AND
PILOCARPINE
PINDOLOL
• Potent βadrenergic antagonist with intrinsic
sympathomimetic activity
• 0.5-1%
NADOLOL
• NON SELECTIVE β BLOCKER
• 1-2%
• DIACETYL NADOLOL
• LOWER INCIDENCE OF TOLERANCE
BEFUNOLOL
• 0.25-0.5%
ADMINISTRATION
• Individuals with darker irides require higher
concentrations of timolol
• Non specific binding of drug to pigment
FREQUENCY
• IOP lowering effect peaks at 2 hrs and lasts for
24 hrs
• Twice daily
• On discontinuation-no increase significantly
till 4th day
• Effect seen till 14 days
• Melanotic tissur and slow release
LONG TERM EFFICACY
• the pressure responsiveness to timolol will
decrease with continued administration.
• Occurs in two phases, which Boger called
short-term escape and long-term drift.
Short term escape
• dramatic reduction in IOP with the initiation of timolol
therapy
• rises during the next few days and plateaus at a
maintenance level
•
• EXPLANATION-number of β-receptors in ocular tissues
increases during the first few days of timolol therapy
•
• In any case, it is good clinical practice to wait
approximately 1 month after initiating timolol to determine
the efficacy of therapy
LONG TERM DRIFT
• slow decline in pressure response to timolol, usually
beginning 3 months to 1 year after starting treatment
• some regain responsiveness to timolol after a washout
period
• a treatment strategy of pulsatile therapy, in which 0.5%
timolol is given for 6 months and then alternates with
dipivefrin for 2 months, was studied and shown to
minimize long-term drift compared with continuous
use of timolol
MULTIPLE AGENT FORMULATIONS
• BRIMONIDINE 0.2% + TIMOLOL 0.5%
• DORZOLAMIDE 2% + TIMOLOL 0.5%
• PILOCARPINE 2-4 % + TIMOLOL 0.5%
SIDE EFFECTS
• does not affect the pupillary size or accommodation.
• The tear film may be altered in patients who have low
baseline tear flow
• Chronic therapy with timolol has been shown to affect
the mucus layer of the tear film
• Burning and conjunctival hyperaemia a/w superficial
punctate keratopathy and corneal anesthesia
• serious side effect -ocular cicatricial pemphigoid
• chronic inflammation from the irritating effects of
the antiglaucoma medications and/or
preservatives
The most troublesome ocular reaction that has
been reported with metipranolol is a
granulomatous anterior uveitis, characterized by
mutton-fat keratitic precipitates, flare and cells,
and IOP elevation
SYSTEMIC TOXICITY
• MORE THAN OCULAR REACTIONS
• SYSTEMIC ABSORPTION-8 MINS
• the role of punctal occlusion
CARDIOVASCULAR EFFECT
•
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BRADYCARDIA
WEAKENS MYOCARDIAL CONTRACTILITY
ARRTHYTHMIAS
SYNCOPE
MORE WHEN CONCURRENTLY USED WITH
OTHER DRUGS SUCH AS QUINIDINE AND
CALCIUM CHANNEL BLOCKERS
RESPIRATORY EFFECTS
• CONTRACTION OF BRONCHIAL SMOOTH USCLE
• BRONCHOSPASM AIRWAY OBSTRUCTION
• ESP IN ASTHAMATICS
• more common in young children, and caution
must be taken by nursing mothers, because high
levels of timolol were found in the milk of a
mother receiving topical timolol
•
CENTRAL NERVOUS SYSTEM
• depression, anxiety, confusion, dysarthria,
hallucinations, lightheadedness, drowsiness,
weakness, fatigue, tranquilization, dissociative
behavior, disorientation, and emotional
lability
CHOLESTEROL LEVELS
• 0.5% topical timolol twice daily for 2 months,
without nasolacrimal occlusion, has been
shown to decrease plasma HDL cholesterol
levels, which increases the risk of coronary
artery disease
SYSTEMIC REACTIONS
• gastrointestinal distress (nausea, diarrhea, and
cramping)
•
• dermatologic disorders (maculopapular rash, alopecia,
and hives) and sexual impotence
•
• exacerbation of myasthenia gravis
•
• altered response to hypoglycemic episodes in diabetic
patients, which may mask the awareness of the attack
α ADRENERGIC RECEPTOR
ANTAGONISTS
• THYMOXAMINE
• MIOSIS BY INHIBITION OF DILATOR MUSCLE
without influencing the ciliary muscle-induced
facility of aqueous outflow
• does not cause shallowing of the anterior
chamber or ciliary spasm, it provides safe,
rapid reversal of the effects of an adrenergic
mydriatic drug.
• 0.1% to reverse mydriasis from phenylephrine
• role in management of angle-closure
glaucoma
• miosis despite pressure-induced ischemia of
the iris sphincter and not increasing the
posterior vector force of the iris, which might
aggravate the pupillary block
• thymoxamine produces miosis without
affecting the ciliary muscle-controlled facility
of outflow, it can break an angle-closure attack
• narrowing of the palpebral fissure in many
patients with eyelid retraction
• especially cases secondary to thyroid disease,
• value in the diagnosis of thyroid eye disease
and possibly in the medical treatment of
eyelid retraction (0.5%)
DAPIPRAZOLE
• reversal of mydriasis after an ocular
examination
• BUNAZOSIN
• lower IOP in normal subjects in single doses of
0.025% to 0.2% and was effective for 1 week in a
concentration of 0.1%
• increased uveoscleral outflow
• cause miosis, ptosis, and conjunctival hyperemia
PRAZOSIN
• topical administration of 0.001% to 0.1%
prazosin causes a dose-related lowering of IOP
by reducing aqueous humor formation
CORYNANTHINE
• Selective α1-adrenergic antagonist
• increase in uveoscleral outflow
LABETALOL
• combined α1 and α2-adrenergic blocking
agent
• poor ocular hypotensive effect in human eyes
THANK YOU !