Ocular pharmacology

Ocular pharmacology
Dr. Ahmed Omara

Contents
• Pharmaco-kinetics
• Pharmaco-dynamics
• Routes of drug administration
• Preservatives
• Drugs
Pharmacology

Pharmaco-kinetics
= drug trafficking in the body
• Pharmaco-kinetics: Study of the factors that determine the
relationship between drug dosage & change in concentration
over time in a biological system.
Absorption  Distribution  Metabolism  Excretion
• Bio-availability: Amount of drug that reach systemic circulation
& become available to site of drug action.
Pharmacokinetic

How to  the bio-availability of a drug?
1.  Concentration [limited by solubility & tonicity]
2. Add surfactant e.g. benzalkonium chloride [ permeability of cornea]
3. Osmotics [Alter tonicity]
4.  pH [ non-ionized (lipid soluble) form of drug   penetration]
5.  Viscosity [e.g. methyl cellulose & poly-vinyl alcohol   Contact time]
6.  Contact time [ gel or ointment]
7. Punctal occlusion (e.g. by closing punctum after drop instillation  
drainage )
8.  Frequency
PharmacologyPharmacokinetic

1. Absorption
Depends on:
1. Diffusion
2. Carrier molecule = facilitated diffusion: NOT against concentration gradient
3. Pinocytosis
4. Active: against concentration gradient
Pharmacokinetic

1. Diffusion: depends on Solubility:
• Lipid soluble (= non-ionized = non polar): have higher
penetration
• Water soluble (= ionized = polar): have lower penetration
N.B. Solubility of uncharged substances also depend on?
Chemical nature of drug.
e.g. Streptomycin & aminoglycosides (uncharged) has high
hydrogen bonding group make them hydrophilic!
Pharmacokinetic

Fick’s law of diffusion
Pharmacokinetic

Factors affecting absorption & bio-
availability from gut
• G.I motility
• Food (e.g. tetracycline forms insoluble salt with Mg/Ca)
• pH (Penicillin becomes inactive)
• Absorptive area (crhon's disease  absorptive area)
• Intestinal blood flow
• Flora
• Entero-hepatic circulation
Pharmacokinetic

Examples for prodrugs
• Dipivefrin (propine) : Pro-drug of epinephrine (Penetration x 17)
• Nepafenac (Nevanac): Pro-drug of amfenac
Pharmacokinetic

2. Distribution
• Biological half life (T1/2) :
‫النص‬ ‫فيها‬ ‫بيقل‬ ‫الدوا‬ ‫تركيز‬ ‫اللي‬ ‫الفترة‬
(‫اليوم‬ ‫ف‬ ‫مرة‬ ‫كام‬ ‫هيتاخد‬ ‫الدوا‬ ‫هنعرف‬ ‫منها‬)
• Clinical: in ttt we need to reach steady state plasma concentration
‫دي‬ ‫للمرحلة‬ ‫نوصل‬ ‫عشان‬ ‫لفترة‬ ‫الدوا‬ ‫هناخد‬ ‫نوصلها‬ ‫عشان‬
‫ناخد‬ ‫أو‬
Loading dose
Pharmacokinetic

Factors affecting distribution
1. Physico-chemical properties of drug
• Water/lipid solubility
• Molecular size
2. Binding to plasma membrane
3. Binding to tissue proteins
4. Blood flow to tissue
Pharmacokinetic
 plasma protein  plasma protein
Effect 
(low volume of distribution
‫هيروح‬ ‫مش‬ ‫الدم‬ ‫ف‬ ‫هيفضل‬
‫التيشوو‬

Example renal failure

Distribution to eye is limited by blood ocular barriers
Pharmacokinetic

Blood ocular barrier [ ciliary epithelium – iris vessels
– RPE & retinal vessels ]
= Blood aqueous barrier + Blood retinal barriers
Barrier to MOST molecules EXCEPT lipophilic molecules
N.B. Passage of molecules  in inflammation & injury
Example of drugs that can penetrate barrier:
• Antibiotics: Ciprofloxacin – chloramphenicol
• NSAID – SAID
Example of drugs that can NOT penetrate barrier:
• Fluorescine dye (So, it is used to test integrity of retinal circulation)
• Drugs that bound to plasma proteins

3. Metabolism
Lipophilic drugs Change in liver into hydrophilic or inactive drug for
easily excretion
Site of metabolism: Mainly SER of liver cells
Phase I = Modification
• Microsomal enzymes: e.g. Cytochrome P 450 (microsomal) [Heam-protein ]
• Non-microsomal: MAO - COMT
Phase II = Conjugation with:
• Glucouronic acid
• Glycine
• Glutamate
• Sulpher (sulphonation)
• Acetate (acetylation)
Pharmacokinetic
CYP = Cytochrome P 450
[ its reduced form when combine with CO
 product whose absorptive peak is 450
nm]
Cytochrome P 450 is a heam-protein
Applied: CYP is source of iron in:
Stocker’s line – Fleisher ring

Drugs acting on microsomal enzymes
Drugs acting on microsomal enzymes
+ -
Rifampicin Isoniazide
Griseofulvin Chloramphenicol
Metronidazol
Barbiturate
Phenothiazine
Phenytoin
Nicotine
Warfarine
CO Pharmacokinetic

Factors affecting metabolism
• Age:  with age
N.B. Conjugating enzymes are deficient in neonates.
• Smoking 
• Alcohol
• Nutritional state
• Genetics :
- G6PD deficiency e.g. vitamin K, aspirin, chloroquin
- Suxamethonium if patient does NOT have its hydrolysis
Pharmacokinetic

Metabolism of drugs inside eye
Pharmacokinetic
Role Site
Keton reductase Metabolism of timolol & propranolol
analogues
Corneal epithelium
Lens
Iris / C.B
Estrases Activation of ester drugs Anterior segment
Classic
Phase I Oxidation (by cytochrome P450) C.B.
Phase II Conjugation (by glucuronidase)
N.B. Drugs that are good substrates for these enzymes may suffer
substantial degradation during absorption, in the metabolically active sites
( Corneal endothelium – N.P.E. of iris & C.B.)

Excretion
1. Kidney excretion:
- Filtration (20%) to substances:
* Small size (irrespective to their solubility)
* NOT bound to plasma protein
- Secretion
- Re-absorption
2. Bile excretion: e.g. rifampicin
• Conjugated in liver  intestine  stool
 entero-hepatic circulation
Pharmacokinetic

Pharmaco-dynamics
= Drug handling by the body
Study of biochemical & physiological effects of drugs &
their mechanism of action
Pharmaco-dynamic

Definitions
Efficacy Potency
Maximal response it can give. Amount of drug required to give
desired response
‫يجيبها‬ ‫ممكن‬ ‫درجة‬ ‫أعلى‬ ‫يحقق‬ ‫عشان‬ ‫يجيبها‬ ‫اللي‬ ‫الدرجة‬
‫عاوزينه‬ ‫احنا‬ ‫اللي‬ ‫المفعول‬
N.B. Some drugs may be efficacious but NOT potent (requiring large dose)
Pharmaco-dynamic

Definitions
* Tolerance:  efficacy of drug with time
* Therapeutic index: Method to compare between different
antibiotics.
i.e. A measure of relative effective (therapeutic) concentration
of antibiotic at a target site against a target organism.
* Inhibitory quotient (IQ): The most potent antibiotic has the
lowest MIC (minimum inhibitory concentration) or highest IQ.
Pharmaco-dynamic

Routes of drug administration
1. Topical
2. Injection
- Peri-ocular (Sub-conjunctival / sub-tenon / retro-bulbar / peri-bulbar )
- Intra-ocular (Intra-cameral / Intra-vitreal)
3. Systemic (Oral – S.C – I.M – I.V)
Routes

Route Advantage Disadvantages
Topical Easy for patient
Injection -  local concentration
in the wanted site
-  Duration of action
-  Systemic side
effect
- Can be used in drugs
with poor penetration
e.g. antibiotics
- NOT Easy for patient
- Painful
- Risk of local complication
Systemic Easy for patient - Drug must be able to pass blood
ocular barriers
- Systemic side effect
Routes

Injections1. Subconjuctival injection
Method:
• Passing needle through skin of lid between conjunctiva & tenon's capsule
• Passing needle through inferior fornix between conjunctiva & tenon's capsule
2. Subtenon injection
• NOT good as sub-conjunctival (less drug delivery + greater risk) !
3. Retro-bulbar injection
• Use:
• Anesthesia: Lidocaine: prior to surgery
• Alcohol or chloroprmazine: as pain killer in cases of blind painful eye.
• TTT of optic neuritis Routes

Injections
4. Intra-cameral injection (into A.C.)
Example :
- injection of visco-elastic substance during cataract surgery
- Injection of adrenaline …
5. Intra-vitreal injection
Use:
♣ Injection of antibiotic: in endopthalmitis
♣ Injection of anti VEGF
♣ Injections in TTT of CMV
Routes

TTT of CMV
Routes
 Combination between
AZT (Zidovudine)Ganciclovir (80% responds to initial
TTT)
NO direct action on CMV
-  Immunity
-  HIV enhancement of CMV
infection
AntiviralAction
B.M suppression!
‫الدم‬ ‫خاليا‬ ‫تصنع‬ ‫أدوية‬ ‫ويتاخد‬
S.E
 Maintenance therapy : Cidofovir (DNA polymerase inhibitor)‫أسبوعيا‬ ‫مرة‬
N.B. Foscarnet (Safer in combination with AZT)
S.E. renal toxicity 30 %

TTT of CMV
 Maintenance therapy : Cidofovir (DNA polymerase inhibitor) ‫أسبوعيا‬ ‫مرة‬
• N.B. Foscarnet (Safer in combination with AZT)
• S.E. renal toxicity 30 %
Routes
 Combination between
AZT (Zidovudine)Ganciclovir (80% responds to initial
TTT)
NO direct action on CMV
-  Immunity
-  HIV enhancement of CMV
infection
AntiviralAction
B.M suppression!
‫الدم‬ ‫خاليا‬ ‫تصنع‬ ‫أدوية‬ ‫ويتاخد‬
S.E

Topical drugs
Absorbed trans-corneal or conjunctival/episcleral
Forms:
- Solution = drops ‫األشهر‬
- Ointment
- Slow-release preparations (Ocu-sert / collagen shield)
- Spray
- Particulates
- Liposomes
- Stripes (Fluorescine – Rose Bengal)
- Lid scrubs
Routes

Topical drugs concentration
1% solution = 1 gm / 100 mL = 10 mg/mL
• Example: how much atropine is contained in 5 mL of 2%solution?
2% = 2gm/100mL = 20mg/mL = 100mg/5mL
Routes

Ointment
Hydro-carbon + oil + lanolin + polymer (poly-vinyl alcohol or methyl-
cellulose)
- Side effects:
Blurring of vision
Contact dermatitis (d.t. preservative)
Routes

Ocu-sert
(controlled concentration over time)
Examples:
- Pilocarpine
- Carboxy-methyl cellulose
Routes
Criteria of oculoserts
‫فيها‬:‫معقمة‬-‫األكسجين‬ ‫و‬ ‫النظر‬ ‫ع‬ ‫بتأثرش‬ ‫ما‬
‫استخدمها‬:‫سهلة‬–‫مريحة‬–‫العين‬ ‫م‬ ‫بتقعش‬ ‫ما‬

Collagen shield
- Antibiotics
- Dexamethason
- Prednisolon
- Cyclosporine A
Routes

Factors affecting topical drug absorption
1. Drug factors
- Volume ( volume:  residency in conjunctival sac)
- Formulation
Drug viscosity:  viscosity   residency in conjunctival sac
Drugs  lacrimation   residency in conjunctival sac   clearance
♣  pH   lacrimation …….
♣  Tonicity ( stinging   lacrimation …….. )
♣ Direct effect on lacrimation ………
Perservatives
Routes
 Tonicity e.g. phosphate
buffer   stinging 
 lacrimation …

Factors affecting topical drug absorption
2. Personal factors
- Tears: affected by:
♣ Environmental condition (Temperature / Humidity)
♣ Blinking rate
♣ Stability
♣ Nature of eye drops (Drugs  lacrimation  ……… )
- Conjunctiva: drug absorption  with V.D. (absorption to systemic circulation)
- Cornea (The major barrier against penetration of topical drugs d.t. tight junction) 
Drugs must be lipophilic to pass through epithelium (Intra-cellular NOT inter-
cellular)& hydrophilic to pass through stroma. (endothelium [lipophilic] is NOT rate
limiting)
Routes

Notes: Drops & conjunctival sac
 Tear film = 7-8 microL
 One drop = 50 microL
 Conjunctival sac capacity = 10-30 microL (= 20 % of drop)!
 Tear turnover = 16 % / minute
ONLY 50% of drug that reach conjunctival sac is present 4
minutes later (10% of drop)!

‫للفهم‬ ‫محاولة‬

Notes: corneal penetration
♣ Biphasic drugs (Lipophilic + hydrophilic) has the great permeability
through cornea. E.g. tropicamide / cyclopentolate
♣  permeability in (epithelial defect or benzalkonium )
♣ Stroma has a diffusional rate = 1/4 that of aqueous system
♣ NSAID & pilocarpine accumulate in cornea. 
♣ Lipophilic drug reservoir: Corneal epithelium consists 2/3 of plasma
membrane mass of cornea, so acts as large store for lipophilic drugs
whose release rate into aqueous depends on their speed in altering to
hydrophilic phase
♣ If ionized drug can penetrate cornea d.t. epithelial defect, it is bound to
melanin of iris & C.B.  SLOW release (Prolonged but  effect )
- Sclera (Higher permeability than cornea)
Routes

Notes: Drugs at A.C
Once drugs enter A.C., they are eliminated by aqueous turnover (=1.5 %/min)
Aqueous half life = 46 minutes.
 If drug half life < 46 minutes  dug metabolism & reuptake = 
elimination from eye   availability of drug to intra-ocular structures.
 If drug half life > 46 minutes  significant tissue binding of drug = 
elimination from eye
Routes

Notes: Drugs at vitreous
Topical medications penetrate into vitreous poorly, as:
1. They must diffuse against aqueous gradient
2. SLOW diffusion of drug through vitreous
This explains why topical antibiotics do NOT achieve minimal
inhibitory concentration (MIC) in vitreous. 
Routes

Note: NLD & drugs
NLD: Make drugs to be absorbed systemic
N.B. To  systemic absorption: close the punctum for 5 minutes after
drops administration
Routes

Preservatives
• Aim: Keeps ointment & drops sterile
• Side effects: Most of them disrupt tear film
• Examples:
o Benzalkonium chloride
o Chlorbutol
o Thiomersal/Phenyl-mercuric nitrate
o Cholohexidine
o Sorbic acid
preservatives

Benzalkonium chloride
Cationic preservative = Surfactant preservative
• Role:
♣ Bactericial: Attaches to bacterial cell wall  affecting wall integrity  
permeability  rupture
♣  Drug penetration (by affecting corneal integrity)
• S.E:
- Cellular damage
- Allergy
N.B. Benzalkonium is effective at alkaline pH (8)
N.B. Benzalkonium is inactivated by soaps & salts e.g. Mg or Ca
So, some of contact lens solutions contains EDTA (chelating agent)
preservatives

Notes: preservatives
• Chlorbutol
Side effect:  O2 utilization by cornea  epithelium desquamation
• Thiomersal/Phenyl-mercuric nitrate
Side effect:
- Allergy
- Deposits ‫الزئبق‬
preservatives

Reconstituting tear film
1. Tear substitutes [ with preservative OR preservative free ]
Content: inorganic ions (0.9 % NaCl) + polymers
Aim:
*  Wettability
*  Retention time
Examples:
* Hydroxy-methylcellulose
* Poly-vinyl alcholol (has additive surfactant properties = More
stabilization)
* Poly-acrylic acid (Carbomers) [Hydrophilic gel] ‫أقل‬ ‫مرات‬ ‫عدد‬
* Hyalourinic acid (has greater retention than cellulose)
Drugs

Reconstituting tear film
2. Mucolytics: e.g. acetyl cystein
Dissolve mucous thread problem in keratoconjunctivitis sicca
Drugs

Anti-allergic drugs
• Anti-histaminic
• Vaso-constrictor
• Mast cell stabilizer
Drugs
Mast cell
stabilizer
Vaso-
constrictor
Anti-
histaminic

1. Vaso-constrictor
Example
• Naphzoline (Naphcon A)
• Pheniramine maleate
N.B. Vaso-constrictors can cause rebound redness! (on chronic use)
Drugs

2. Anti-histaminic
H1 receptor stimulation H1 receptor inhibition
Action  V.D   permeability   odema
  hyperemia
  Mucous secretion
 Smooth muscle contraction & bronchospasm
 odema
 hyperemia
 itching
 mucous secretion
+ ve chronotropic action d.t. direct effect on heart
receptor & by baro-receptor reflex d.t. V.D. 
Drugs
Side effect: of anti-histaminic: sedation
NOW, there are non-sedative anti-histaminics e.g. terfenadin

Topical anti-histaminic
1. Levo-carb-astine (livostine)
2. Emed-astine (Emadine)
Drugs

H1 blocker + Mast cell stabilizers
1. Nedocromil (Alocril)
2. Pemirolast (Alamast)
3. Ketotifen (Zaditor / Alaway)
4. Azelastine (Optivar)
5. Epinastine (Elestate)
6. Bepostatine (Bepreve)
7. Alacaftadine (Lastacraft)
Drugs

3. Mast cell stabilizers
 Actions:
 Prevent mast cells de-granulation
 Prevent release of histamine
  Phospho-di-estrase activity (facilitator of mast cell de-granulation)
 Inhibit activation of (Eosinophil - Neutrophil – Monocytes)
Drugs
Example Action Potency
Sodium cromoglycate
(opticrome)
Mast cell stabilizer 1
Lodoxamide (Alomide)
Mast cell stabilizer +
Eosionophil suppressor
x 2500

Mast cell stabilizer
Used as a prophylaxis NOT as a TTT, because:
1. They does NOT interfere with binding of antigen to previously sensitized
cells
2. NO anti-histaminic action
Drugs

Ecosanoids
Eico = 20 [as their origin is arachidonic acid (which is 20-carbon fatty acid)] 
Formation:
Drugs

Non-SAID
• Action: Stop prostaglandin synthesis (‫والوحش‬ ‫الحلو‬ ‫بتوقف‬
* Topical (e.g. diclofenac , ibuprofen)
- Prevents peri-operative miosis
-  Post-operative inflammation
* Stystemic (e.g. indomethacine)
-  Pain
-  Inflammation (e.g. scleritis / uveitis )
Drugs
N.B. Anti COX II : preserve PG that protects stomach

Non-SAID
Classes of non-SAID:
• Salicylates: acetyl-salicylic acis (ASA), diflunsial, salicylamide
• Acetic acids: indomethacin (indomtacin), diclofenac (voltaren), sulindac,
etodolac, ketorolac (Acular, Toradol), nepafenac (Nevanac), bromfenac
(Xibrome, Bromday)
• Phenylalkanoic acids: ibuprofen, suprofen (Profenal), flurbiprofen (Ocufen),
naproxen, fenoprofen, ketoprofen
• Cyclooxygenase-II inhibitors: celecoxib (Celeberx)
Drugs

‫العنوان‬ ‫عارف‬ ‫مش‬ ‫لسه‬
• SAID
• Prostaglandin analogues
Use: TTT of open angle glaucoma
N.B.
* Thromboxane A2 : cause
- V.C.
- Platelet aggregation
* Leucotrienes: [ Involved in inflammation & allergic reactions] cause
- V.C.
- Vascular permeability
- Broncho-constriction
* Prostaglandins: sensitize nerve endings to pain (BUT do NOT themselves produce pain)
Drugs

Serotonin = 5-Hydroxy-tryptamin = 5-HT
Neuro-transmitter at: retina / cortex / GIT mucosa / Platelet
• Formation: Tryptophane (amino acid)     serotonin
• Destruction: by MAO    to urine
• Types: 5-HT 1,2,3,4
• Uses:
• Selective 5-HT2 antagonist: Prevention of migraine attack
• Selective 5-HT3 antagonist:  Pain of migraine attack
Drugs

Glauco-corticoids
Drugs
Plasma cortisol:
- Maximal at 6-8 A.M
- Lowest at mid-night. 

• Classes:
• Ester: Loteprednol
• Keton: ‫الباقي‬
• Preparations (Keton):
• Phosphate (hydrophilic) 
• Alcohol (Biphasic) 
• Acetate (more biphasic = best penetration)  
• Potency: Increased by 1-2 double bond(s)
Drugs

Forms
• Topical
• Injections (Sub-conjunctival / Sub-tenon / Intra-cameral / Intra-vitreal )
• Systemic ( oral – I.M. – I.V )
Drugs
Oral dose of 7.5 mg dexamethason results in intra-vitreal concentration of
therapeutic level

Mechanism of action
It enters cell membrane without need of receptors. 
 Anti-inflammatory & immune-suppressive
 Anti-allergic :  allergic type I hyper-sensitivity
Drugs
Anti-
inflammatory
Anti-
immunity
Anti-allergic

Mechanism of action
 Anti-inflammatory & immune-suppressive
•  vascular permeability   exudation
• Inhibition of phospholipase A2   inflammatory mediators (PG / Leucotrienes /
Thromoxane A2 )
• Inhibition of arachidonic acid release
• Inhibition of histamine release
• Inhibition of neo-vascularization
• Inhibition of fibroblasts
•  BOTH number & function of leucocytes
• Inhibits release of lyzosomal enzymes
•  Catabolism of immune-globulin
Drugs
N.B. It causes neutrophilia!! but inhibits neutrophil migration
N.B.  lymphocytes ( T cells > B cells )

Mechanism of action
•  Anti-allergic :  allergic type I hyper-sensitivity
•  Histamine production
•  Prostaglandin production
Drugs
Systemic cortisone does NOT affect IgG (mediator of auto-immune
response) NOR IgE (mediator of allergic response)

Uses of cortison
• Lid inflammation
• Conjunctival inflammation
• Corneal inflammation
• Hyphema
• Iridocyclitis
• Endophthalmitis
• Macular odema
• C.N.V
Drugs

Side effects ‫الباقيين‬ ‫مع‬ ‫زبطها‬ ‫ابقى‬
Side effects: Depends on duration & potency
• Posterior sub-capsular cataract ( lens hydration, Na /  K, urea,
glutathione)
• Glaucoma (GAG theory) …………
•  Incidence of bacterial infection
• Reactivation of viral infection
• Inhibits peripheral glucose utilization
•  Protein breakdown
Drugs

Steroid increasing IOP:
Dexamethason > Prednisolone > Flurometholone > Hydro-cortisone > Tetra-hydro-
triamicilone > Medrysone
Steroid with less IOP elevating potential:
Rimexolone (Vexol) & Loteprednol (lotemax, Alrex)
N.B. After 6 weeks of dexamethason therapy
42 % have IOP > 20 mmHg
6 % have IOP > 31 mmHg

Side effects of topical steroid
1. Mild ptosis
2. V.C. of conjunctival blood vessels
3. Ocular discomfort
4. Corneal thickening
5. Inhibition of corneal epithelial healing & neovascularization
6. Mild mydriasis (1 mm)
7. Refractive errors
Drugs

Side effects of peri-ocular steroid
Locally:
• Glaucoma
• Cataract
• Proptosis
• Retinal & choroidal vessels occlusion
Systemic:
• Cushing's syndrome
• Systemic hypertension
Drugs

‫التصنيف‬ ‫عارف‬ ‫مش‬

5-fluorouracil (5FU)
Fluorinated pyrimidine
Action: antiproliferative effects
Mechanism of action:
‫هيتزبطوا‬ ‫دول‬ ‫لسه‬
• Incorporation of 5FTJ derivatives into D1STA will also interfere with RNA processing
and function.
• 5FU may also be incorporated directly into RNA disrupting protein synthesis.

Mechanism of action of 5-fluorouracil (5FU)
5-fluro-uracil
5-fluoro 2-deoxyuridine 5'- monophosphate (FdUMP)
The active
form
Competitive inhibition with thymidylate synthetase in S phase cells
Inhibit DNA synthesis

5-fluro-uracil
5-fluoro 2-deoxyuridine 5'- monophosphate (FdUMP)
The active
form
by intracellular kinases
5-fluoro 2-deoxyuridine 5'- triphosphate (FdUTP)
Triphosphate is incorporated into DNA instead of thymine rendering it unstable

Side effects:
- Corneal epithelial toxicity d.t. its effect on rapidly dividing cells.
Dose given at the time of glaucoma filtration surgery  inhibit fibroblast
proliferation for approximately 4-6 weeks.

Mitomycin C
Naturally occurring? alkylating agent with antibiotic and antineoplastic
properties.
• Derived from: Streptomyces caespitosus.
• Action:
- Anti-proliferative effect on cells irrespective of their stage in the cell cycle,
[ although it has a maximal effect on cells in the G and S phases]
• Epithelial toxicity is not usually associated with the use of mitomycin C in
glaucoma filtration surgery.
Despite the permanent antiproliferative effect of mitomycin C on fibroblasts (it is 100 times
more potent than 5-fluorouracil) it does not inhibit their migration or attachment.

Mnemonics
Mitomycin C5 FU
Any phase
(Maximally S or G
phase)
S phaseStage of cell cycle
affection
Mitomycin 100 times potentPotency
Permanent4-6 weeks
(5 weeks)
Effect on fibroblast
NOYesEpithelial toxicity

Immuno-suppressive drugs
Drugs
Drugs controlling immune response (especially T lymphocyte)

Groups of immune-suppressives
Drugs
Group Examples
Cyto-toxic Anti-metabolites
( Inhibition of purine ring bio-synthesis)
Methotrexate
Azathioprine
(imurane)
Alkylating agents
(Create cross linking between DNA strands  inhibition
of mRNA transcription  inhibition of DNA synthesis)
Chlorambucil
(Leukran)
Cyclophosphamide
(Cytoxan)
Cyto-static Steroid
Immuno-modulator Cyclosporin
Others Colchicine
(Inhibition of leucocyte migration)
Use: Prevention of Behcet's recurrence
Oncolytic agents

Uses
1. Prevention of allo-graft rejection
2. Auto-immune diseases
3. Chronic allergy
4. Endogenous uveitis
Drugs

Cyto-toxic drugs
Drugs
Action Side effects
Chlorambucil Sterility
B.M. suppression
Azathioprine
(Purine analogue)
Inhibits purine synthesis  blocks DNA & RNA
synthesis
B.M. suppression
GIT upset
Cellcept
(Mycofenolate mofetil)
Block pathway of purine synthesis
Methotrexate
(Folate analogue)
Folate metabolism
Di-hydro-folate reductase
T-cell function
De-oxy-thymidine monophospahte nucleotide
B.M. suppression
GIT upset
Teratogenic 
Toxicity (Kidney – Liver – respiratory)
Periorbital odema
 ESR
Cyclophosphamide Hemorrhagic cystitis (oral > I.V)
Prevented by high water intake (oral or
I.V)
Renal transitional cell tumor
Sterility
B.M. suppression

Others
Drugs
Action Side effects
Corticosteroid Block transcription of cytokine
genes
(IL1,2,3,5 – TNFα – interferon
Osteoporosis
Hypertension
Glucose intolerance
Cyclosporin Inhibits IL2 production  inhibits
lymphocytes proliferation &
activation
OF systemic use ONLY
Nephrotoxic
Hypertension
Glucose intolerance
Hyperlipidemia
Hirsutism
Gingival hyperplasia
Peripheral neuropathy
Hepatotoxicity
Hyperuricemia
Tacrolimus Inhibits IL2 ‫سبورين‬ ‫السيكلو‬ ‫زي‬
Cyclosporin /
Tacrolimus :
are available as
topical drugs

== Cyclosporin indication ==
• Topical
 Necrotizing scleritis
 Sjogren syndrome / dry eye syndrome
 Liganeous conjunctivitis
 Atopic kerato-conjunctivitis
• Systemic
 Mooren's ulcer
 Uveitis (in Behcet disease or sympathetic ophthalmia)
 Prevention of corneal allograft rejection
 Ocular cicatricial pemphigoid
 Thyroid eye disease
Drugs

== Biologics ==
TNF α : [ Mediator in auto-immune disease ]
* Block receptor: Inflixmab
* Neutralization: Etenercept
VEGF : vaso-endothelial growth factor
* Block receptor: x
* Neutralization: Ranibizumab / Aptamers (pegaptanib sodium)
Drugs

Local anesthetics
Drugs reversibly prevent transmission of nerve impulse locally.
• Nature: weak bases (pH = 8-9) 
• Mechanism of action: “Stabilization of membrane”
Reversible block of initiation & propagation of action potential (by
prevention of Na influx)
• Duration of action = 10 – 30 minutes
Drugs

Local anesthetics
• * N.B. Local anesthetic has 2 portions
Drugs
Non-ionized = Non-cationic = Lipophilic Ionized = Cationic = Hydrophilic
‫يخترق‬
Penetrate myelin
‫يخدر‬

Local anesthetics
• So, action depends on pH:
Drugs
In alkaline pH In acidic pH
example NaHCO3 Inflamed wound
Result Lipophilic portion > hydrophilic
=  penetration
Lipophilic portion < hydrophilic
=  penetration
If it can NOT penetrate myelin, it acts on nodes of Ranvier
They act on: Parasympathetic  Sympathetic  Sensory  Motor
Local anesthesia do NOT work in inflamed tissue ? WHY ??
1. Less penetration
2. More blood supply (more escape of the anesthesia)

Side effects
• Local:
• Inhibit wound healing
• Disturb junction between cells  desquamation of epithelium within 5 minutes
• Interfere with metabolism & repair (inhibit mitosis & migration)
• Allergy (Ester ˃ Amides)
• Systemic
• Numbness / tingling
• Dizziness
• Slurred speech
• C.N.S toxicity: convulsion – cardiac depression – respiratory depression
Drugs
So, in infiltrating anesthesia, should be done with:
1. I.V. access
2. Monitor: heart rate – O2 saturation
Local anesthesia should NEVER be administered systemically

Infiltrative anesthesia
Drugs
Peri-bulbar Retrobulbar
Site Outside muscle cone Inside muscle cone
Advantage Less hematoma
Dis-advantage  infiltration of
anesthesia, so it is used
with hyalurindase 150 I.U
to  infiltration (but it 
duration)
3rd
4th
6th
Affected E.O.Ms
motility
- Ptosis
2nd -  Visual acuity
- abnormal pupil
reflex
Conjunctival hemorrhage (Common)

Classes of local anesthesia:
Drugs
Ester-linked Amide-linked
Onset Rapid Slow
Duration Short (as it is susceptible to hydrolysis) Long (More stable) especially in acidic solution !
[ In conjunctival sac (pH = 7.4) only 15 % non-
ionized
Degradation Plasma: cholin-estrase
Liver: hepatic enzymes
Liver: hepatic enzymes
Examples - Benoxinate
- Cocaine
- Procaine 30-40 minutes
- Tetracaine Longer duration
- Proparcaine
- Lignocaine = Lidocaine (Xylocaine) 1
hour
- Mepivacine (Carbocaine) 2 hours
- Bupivacine (Marcaine) 6 hours
N.B. corneal toxicity
Cocaine > Tetracaine > Propracaine
N.B. BOTH classes do NOT necessarily have allergic cross-reactivity

Maximal safe dose of regional anesthesia
• Lidocaine
- 10-15 ml 2% solution (200 mg)
OR - 20-25 ml 2% solution (500 mg) + epinephrine 1:200,000
• Bupivacaine
• 10-15 ml 0.75% solution (150 mg)
Drugs

Epinephrine & anesthesia
1* 1:100,000 epinephrin is added to cause vaso-constriction 
- Retard vascular absorption  retard hydrolysis of anesthesia  
action
-  bleeding
2* Mixture  alter pH (as epinephrine is acidic)   amount of non-
ionized form   penetration
3* Destroyed by heat
Drugs

Drugs
Benoxinate has some anti-microbial effects e.g. against staphylococci, pseudomonas & candida. 

Anti-glaucomatous drugs
1. Cholinergic drugs (parasympatho-mimetics)
2. Adrenergic drugs ( sympatho-mimetics)
3. Adrenergic drugs (Beta blockers)
4. Osmotic agents
5. Prostaglandins
6. Carbonic anhydrase inhibitor
+ Neuro-protectives
Drugs

1. Cholinergic drugs
• Example: pilocarine (1% , 2%, 3%, 4%) : 4 times/day
(or gel once daily before sleep)
• Action:
 Contraction of constrictor pupillae muscle → widening of angle
 Contraction of ciliary muscle → traction on scleral spur → ↑ T.M out flow
Drugs

Side effects of pilocarpine
• Local: allergy +
• Conjunctiva: Follicular conjunctivitis
• Iris:
 Iris cyst d.t. proliferation of iris pigment epithelium [prevented by phenylephrin]
 Posterior synechia
 Miosis [ ↓ night vision ]
 Disturb BAB (blood aqueous barrier)
• Lens: cataract
• Retinal detachment d.t. altered forces at vitreous base d.t. CB contraction → tear
• Myopic shift d.t. spasm if circular ciliary muscles*
• Brow & temporal headache (Normally reversible 2-3 days)*
Drugs

Side effects of pilocarpine
• Systemic: RARE
• Sweating
• Nausea
• Vomiting
• Abdominal colic
• Bradycardia
• Bronchospasm
Drugs

Contraindication of pilocarpine
• Iridocyclitis d.t.:
1. Disturb BAB (blood aqueous barrier)
2. Miosis → posterior synechia
Used cautiously in:
- ‫ورضاعة‬ ‫حمل‬
- Myocardial infarction
- Hypotension
- Hypertension
- Hyperthyroidism
- Peptic ulcer
- Bronchial asthma
- Parkinsonism
Drugs

2. Sympathomimetics
Non-selective
• Adrenaline
• Dipivefrin (propine)
Selective
• Clonidine [Obsolete: pass blood brain barrier → hypOtension]
• Apraclonidine (α agonist)
• Brimonidine (α2 agonist)
Drugs

Apraclonidine (iopidine)
• Used for short term therapy [ it is effect lost after 3 months]
Side effects
Local
- Allergy
- Lid retraction
- Conjunctival blanching
- Mydriasis
Systemic
• Dry eye & mouth
• Headache
• May exacerbate IHD
• hypOtension !
Drugs

Apraclonidine
Contraindicated
• Allergy
• Patient is taking MAO & TCA (tri-cyclic anti-depressants)
Used cautiously in
• ‫حمل‬‫ورضاعة‬
• Orthostatic hypOtension
• Raynaud’s phenomena
• Cardio vascular diseases
• In combination with (BB – antihypertensive – digitalis)
Drugs

Brimonidine (aphagan)
Side effects
Local
- Allergy 10 %
Systemic
• Dry eye & mouth
• Headache
• Fatigue
Drugs
In children:
• Bradycardia
• HypOtension !
• Apnea
• Drowziness
Contraindicated at 1st
year of life as it pass
to CNS

Brimonidine
Contraindicated
• At 1st year as it pass the CNS
Used cautiously in
Cerebral insufficiency
In combination with (CNS depressants as alcohol, barbiturates, opiates …)
‫الديبرشن‬ ‫بيزود‬
Drugs

Adrenaline
Drugs
ContraindicationSide effects
Allergy
Rebound phenomena (VC → VD)
NOT used with contact lensesBlack deposits (adrenaline is
oxidized to adrenochrome)
Narrow angle (it may be closed)Mydriasis
NOT used in aphakic &
pseudophakic
Cyctoid macular odema 30% of
aphakic patients
Used cautiouslyTachycaria / arrythima
Used cautiouslyhypertension
Hyperthyroidism ‫والحمل‬‫والرضاعة‬
used cautiously

3. Beta blockers
Non-selective 1 X 2
• Timolol
• Cartelol
• Levobunolol (Betagan)
Selective B1 blocker
• Betaxolol (Betoptic) [least effective to ↓ IOP]
Drugs
Propranolol is NOT used in TTT of glaucoma ?
As it is strong membrane stabilizer (act as a local anesthetic)

Timolol
Non-selective BB
• Metabolized by liver
• Relatively α1 antagonists (give additive response if used with pilocarpine)
Drugs
Timolol is stronger than pilocarpine in lowering IOP

Cartelol
Non-selective BB
+ ↑ optic nerve perfusion
• Has intrinsic symoatho-mimetic activity (ISA) that
cause early transient agonist response, so
• ↓ incidence of bradycardia & bronchospasm
• Minimize ↓ of HDL
‫دروبس‬ ‫التوبيكال‬ ‫مع‬ ‫واضحيين‬ ‫مش‬ ‫دول‬ ‫الميزتين‬
Drugs

Levobunolol (Betagan)
Non-selective BB
• 30% ↓ IOP
• Action: 24 hours (but taken also 1 X 2)
Drugs

Beta blockers
Side effects
Local: allergy +
• SPK
• Corneal anesthesia
• Dry eye
• Hypermia
Drugs

Beta blockers
Systemic:
B1 blocker:
• Bradycardia (-ve chronotropic) may → Heart block
[ Some BB with intrensic sympathetic activity are less likely to cause bradycardia]
• Hypotension (-ve inotropic)
[ NOT orthostatic hypOtension because α receptor that control vascular resistant is not affected]
• Congestive HF
• Worsening of PVD
• Fatigue, depression, confusion
• Hallucinations
• Impotence + ↓ libido
• Exacerbation of myasthenia gravis
Drugs
Heart
CNS
Lipid soluble BB cause bad dreams ˃ water soluble
BB
As lipid soluble drugs pass blood brain barrier

Beta blockers
Systemic:
B2 blocker:
• Brocnhospasm
• Respiratory failure
Drugs
Less with selective BB as betaxolol, but we do NOT give it to
asthamtics
↓ HDL → ↑ risk of MI
↓ HDL ?? WHY ??
1. Inhibition of lipoprotein lipase (break down chylomicron & VLDL)
2. Inhibition of acetyl transferase (incorporate cholesterol onto HDL)

Beta blockers
Contraindicated
• Cardiac patients
• Asthmatic patients
• Myasthenia gravis
Used cautiously in
‫ورضاعة‬ ‫حمل‬
Hyperthyroidism ???? ‫الثيرويد‬ ‫مع‬ ‫بنستخدمه‬ ‫واحنا‬ ‫ازاي‬
Drugs
Used cautiously with diabetic patients, WHY ?
1.↓ Glycogenolysis & glauconeogenesis
2.↓ Normal physiologic response to hypoglycemia

4. Osmotic agents
• Mechanism of action:
Osmotic agent remains in blood → ↑ osmolarity → creating osmotic gradient
between blood & vitreous → water is drawn from vitreous → ↓ IOP
Drugs
Osmotic pressure depends on number rather than size of solute particles in a solution
(i.e. LOW molecular weight solutes exert a greater osmotic effect per gram)
Intact blood aqueous barrier (BAB) is a must for the work of these drugs
If disturbed BAB e.g iridocyclitis, these drugs will be of limited value

Osmotic agents
• Uses:
When we need to ↓ IOP temporarily e.g.
1. Acute congestive glaucoma
2. Prior to I.O surgery with ↑ IOP e.g. AC lens dislocation
Drugs
Osmotic agents should be given fairly rapidly !
& the patient should NOT subsequently be given fluid to quench thirst

Examples of osmotic agents
OralI.V
GlycerolMannitol 20 %
Iso-sorbidUrea
Drugs
Osmotic agents can be used topically for corneal odema
 Glycerine (opthalmogan)
 Muro128: hypertonic saline 2.5 – 5 %

Mannitol 20% solution
• Dose: 1gm / kg or 5ml/kg (I.V slowly over 20-40 minutes)
• Peak action within 30 minutes
• Remain unbound to protein in extracellular compartment
• Excreted by kidney SLOWLY (90% unchanged by kidney)
Drugs
NOT given orally ?? NOT absorped by GIT
Mannitol ↓ IOP by additional action ?
D.t. hypothalamic efferents travelling in optic nerve
F
Take care
in renal
failure

Mannitol side effects
Draw ICF into EC spaces !
1. Circulatory overload [especially in renal failure]
• Congestive heart failure
• Pulmonary odema
• Urine retention (If prostatic enlargement)
[ i.e. catheterization may be necessary]
2. Cellular dehydration
• Headache
• Dizziness
• Confusion
3. Back ache Drugs

Urea I.V.
• Distributed allover the body (high solubility) [ EC & IC]
• Excreted by kidney (in urine)
Drugs
NOT commonly used ??
Extravasation → tissue necrosis

Glycerol
• Dose: 1gm/kg or 2ml/kg (orally)
• Metabolized by liver [ so, safe in renal failure]
Drugs
Given orally ?? Rapidly absorped by GIT
Although glycerol is metabolized to glaucose, it may be given to well-
controlled diabetics
Glyecerol (unlike mannitol) penetrates more rapidly into inflamed eye
& penetrates poorly to un-inflamed eye !

Side effects of glycerol
‫أوي‬ ‫مسكر‬
• Nausea – vomiting (so, mixed with lemon juice)
• Hyperglycemia
• Hyperosmotic coma
• DKA
Drugs
‫ويشربه‬ ‫لموون‬ ‫عصير‬ ‫على‬ ‫باحطه‬(‫برتقان‬ ‫مش‬)

Iso-sorbid
• Dose: 1gm/kg or 2ml/kg (orally) [ Minty taste]
• Metabolically inert (NOT metabloized)
• May be given to diabetics without insulin cover
Drugs

5. Prostaglandin (PG F2α)
• Latanoprost (Xalatan)
• Brimatoprost (Lumigan)
• Travoprost (Travatan)
• Unoprostone (Rescula)
• Mechanism of action: ↑ uveo-scleral out flow, HOW ?? May be :
* Up-regulating matrix metalloproteinase
* ↓ C.B muscle fiber extra-cellular matrix resistant
Drugs
‫بروستاجالندين‬ ‫عن‬ ‫عبارة‬ ‫الدوا‬ ‫كان‬ ‫زمان‬..‫مشاكل‬ ‫بيعمل‬ ‫لقوه‬
‫بندي‬ ‫بقينا‬
Prodrug which is activated by hydrolysis at cornea
30 %
reduction
in IOP

Side effects
• Local
Lashes: darkening & lengthening
Hypermia
Iris pigmentation 8-15% (Within 3-12 months) 
d.t. ↑ melanin production NOT ↑ in melanocytes***
• Systemic: Flu-like symptoms
Drugs
Contra-indicated in pregnancy
Used Cautiously at:
- Lactation
- Intra-ocular inflammation !

Latanoprost
Drugs
Half life in eyeHalf life in plasma
3 hours
(as there is NO significant metabolism of it at eye)
17 minutes
[Metabolized by liver]
MCQ

6. Carbonic anhydrase inhibitor (CA)
Sulphonamide derivative**
Found in:
• Proximal convoluted tubules
• RBCs
• NPE of C.B
Amount of CA is 100 times that is needed for aqueous production !!
So, ˃ 99% of CA must be inhibited to achieve ↓ IOP !! *
Drugs

Carbonic anhydrase inhibitor (CA)
NOT metabolized ! Excreted in PCT of kidney → alkaline urine →
1. ↑ risk of calcium phosphate stone
2. ↓ ammonium excretion → ↑ risk of hepatic encephalopathy in
hepatic patients
In circulation:
95 % bounded to plasma proteins
5 % unbounded 50% unionized → cell penetration
50% ionized → NO cell penetration
Drugs
WHY alkaline urine ?? as it ↑ urinary bicarbonate & ↓ urinary citrate

Carbonic anhydrase
• Actions
1. ↓ aqueous formation by:
• ↓ bicarbonate formation
• ↓ amount of Na & Cl entering P.C
2. Improve optic nerve perfusion (CO2 = V.D)
Drugs
H2O + fldjsaf; ‫المعادلة‬ ‫اكتب‬

Forms of carbonic anhydrase inhibitors
TopicalSystemic (Oral/parentral)
Dorzolamide (Trusopt)Acetazolamide (Diamox)
Brinzolamide (Azopt)Dichlorphenamide
Methazolamide
Drugs
Systemic CAI NOT used topically ! As it is hydrophilic
Dorzolamide is:
Water soluble at pH 5 & 9
Lipid soluble at pH 7
This allow it to penetrate cornea

Actazolamide (Diamox)
• Dose: 250 – 1000 mg /day in divided dose
• Onset: 1 hour
• Peak at 4 hours
• Duration: 12 hours
• Peak : 12 hours
• Onset: 1 minute
• Peak: 10 minutes
Tablet 250 mg
Sustained release capsule 250 mg
Vials 500mg I.V.
Extra-vasation → severe pain & tissue necrosis !
As it is highly alkaline (pH= 9.1)
TTT of extra-vacation: Na citrate 3.8% immediately
+ Cold compresses + Plastic surgeon advice
Dose: 2 tablets every 12 hour

Drugs
MethazolamideDicholrphenamide
‫زيه‬1 X 2 or 1 X 3Tablet 50 mg
3 hours1 hourOnset

Use of systemic CAI:
- Short term therapy with acute glaucoma
‫مصايبه‬ ‫عشان‬ ‫كتير‬ ‫بنستخدموش‬ ‫ما‬
-
Drugs
‫زبطه‬Others: idiopathic intracranial HTN
Adjunctive therapy for petit mal epilepsy

Side effects of acetazolamide
1. In eye:
- Transient myopia (d.t. C.B. odema → forward shift of iris & lens → shallow A.C.) √
- Dry eye
2. Systemic: Allergy + Bitter (metallic) taste
- Malaise complex 
 Malaise, fatigue, depression
 Anorexia, loss of weight
 Impotence, loss of libido
- GIT complex
 Nausea, abdominal cramp
 Diarrhea (d.t. local inhibition of CA → ↓ H2O absorption from large intestine)
TTT
Na acetate 2 weeks

‫باقي‬Systemic side effects
- Paresthesia of extremities: tingling of fingers, toes & occasionally at muco-
cutaneous junction
- Headache
- Diuresis
- Metabolic & respiratory acidosis
- Chronic use (Renal calculi – HypOkalemia – hypOnatremia)
- Rarely
 Steven jhonson syndrome
 Blood dyscriasis
o Dose-related B.M suppression (Reversible if drug stopped)
o Idiosyncrasy aplastic anemia (Not dose related)
Drugs
If NO complaint of paresthesia … it mean the patient has a compliance of the drug !!

Used cautiously in:
• Renal impairement
• Liver impairment
• With other drugs as: as acetazolamide potentiates its action
 Salicylate (as it change pH → more salicylate penetration to CNS)
 Folic acid antagonists
 Hypoglycemics
 Oral anticoagulants
 Cardiac glycosides (digitalis) ‫جدا‬ ‫جدا‬ ‫خطر‬
 Hypertensive agents
 Phenytoin (↑ occurrence of osteomalacia)
Drugs

Contraindicated in
• ‫رضاعة‬ ‫حمل‬
• HypOkalemia – HypOnatremia
• Renal stones
Drugs

Side effects of dorzolamide
• Local:
• SPK
• Allergy
• Systemic
• Dizziness
• Nausea
• Paresthsia
• Headache
N.B. Brinzolamide has lower incidence of stinging & allergy
Drugs
Must be used cautiously with corneal endothelium dysfunction as it may precipitate
decompensation ( Consider stopping before cataract operations)

Algorithm of TTT
1. Mono-therapy:
Why PG? [ Once – Low SE – Potent IOP ]
If failed
2. Combined therapy: ……………. (also consider systemic CAI)
If failed
3. Laser
Drugs
PG BB
Alpha
agonist or
CAI (topical)

Combinations
DoseCompositionCombination
1 X 2Dorzolamide
Timolol
Cosopt
1 X 2BrimonidineCombigan
1 X 2PilocarpineTimpilo
1 X 1LatanoprostXalacom
1 X 1TravoprostPuotrav
1 X 1BimatoprostGanfort
Drugs

Special cases in glaucoma TTT
Glaucoma in children
• TTT is essentially surgical (we give only pre-operative medications)
• CAI (1 X 3 ) 5-10 mg /kg/day Oral
• May add (Timolol 0.25 % + pilocarpine 2%)
Contra-indicated:
 Brimonidine
 Osmotic agents
Glaucoma in pregnancy
All drugs affect pregnancy
1st line of TTT is laser trabeculoplasty (Selective is better than argon)
Although the lower potential of success ! Drugs

Autonomic nervous system
Sympathetic
Drugs

• Add your first bullet point here
Drugs

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•Third bullet point here
Group 1 Group 2
Class 1 82 95
Class 2 76 88
Class 3 84 90

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•First bullet point here
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