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

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 Pharmacology

Pharmacokinetic

1. AbsorptionDepends on:1. Diffusion2. Carrier molecule = facilitated diffusion: NOT against concentration gradient3. Pinocytosis4. 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! Pharmacokin

etic

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 Pharmacokin

etic

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 عشانناخد أو

Loading dose

Pharmacokinetic

Factors affecting distribution1. Physico-chemical properties of drug• Water/lipid solubility• Molecular size2. Binding to plasma membrane

3. Binding to tissue proteins4. Blood flow to tissue

Pharmacokinetic

  plasma protein plasma proteinEffect

(low volume of distribution الدم ف هيفضل

التيشوو هيروح مش

Example   renal failure

Distribution to eye is limited by blood ocular barriers

Pharmacokinetic

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 .MetabolismLipophilic drugs Change in liver into hydrophilic or inactive

drug for easily excretionSite 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) Pharmacokin

etic

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 IsoniazideGriseofulvin Chloramphenicol

MetronidazolBarbiturate

PhenothiazinePhenytoin

 

Nicotine    Warfarine  CO Pharmacokin

etic

Factors affecting metabolism

• Age: with ageN.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 Pharmacokin

etic

Metabolism of drugs inside eye

Pharmacokinetic

  Role SiteKeton

reductaseMetabolism of timolol & propranolol analogues

Corneal epitheliumLensIris / 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.)

Excretion1. 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 PotencyMaximal response it can

give.Amount of drug required to

give desired response

يجيبها ممكن درجة أعلى 

يحقق عشان يجيبها اللي الدرجةعاوزينه 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 administration1. Topical2. 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

Routes of drug administrationRoute 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 neuritisRoutes

Injections4. 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 CMVRoutes

TTT of CMV

Routes

Combination betweenAZT (Zidovudine) Ganciclovir (80% responds to

initial TTT) 

NO direct action on CMV- Immunity- HIV enhancement of

CMV infection

Antiviral Action

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 betweenAZT (Zidovudine) Ganciclovir (80% responds to

initial TTT) 

NO direct action on CMV- Immunity- HIV enhancement of

CMV infection

Antiviral Action

B.M suppression!الدم خاليا تصنع أدوية ويتاخد

S.E

Topical drugsAbsorbed 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 concentration1% 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

OintmentHydro-carbon + oil + lanolin + polymer (poly-vinyl alcohol or

methyl-cellulose)- Side effects:Blurring of visionContact dermatitis (d.t. preservative)

Routes

Ocu-sert(controlled concentration over time)

Examples:- Pilocarpine- Carboxy-methyl cellulose

Routes

Criteria of oculosertsو: - فيها النظر ع بتأثرش ما معقمة

األكسجينما: – – استخدمها مريحة سهلة

العين م بتقعش

Collagen shield- Antibiotics- Dexamethason- Prednisolon- Cyclosporine A

Routes

Factors affecting topical drug absorption1. Drug factors- Volume ( volume: residency in conjunctival sac)- FormulationDrug 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 gradient2. SLOW diffusion of drug through vitreous

This explains why topical antibiotics do NOT achieve minimal inhibitory concentration (MIC) in vitreous.

Routes

Note: NLD & drugsNLD: 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 chlorideo Chlorbutolo Thiomersal/Phenyl-mercuric nitrateo Cholohexidineo Sorbic acid

preservatives

Benzalkonium chlorideCationic 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- AllergyN.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) preservati

ves

Notes: preservatives• ChlorbutolSide effect: O2 utilization by cornea epithelium desquamation

• Thiomersal/Phenyl-mercuric nitrate Side effect:- Allergy- Deposits الزئبق

preservatives

Reconstituting tear film1. Tear substitutes [ with preservative OR preservative free ]

Content: inorganic ions (0.9 % NaCl) + polymersAim: * Wettability* Retention timeExamples:

* 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) Drug

s

Reconstituting tear film2. Mucolytics: e.g. acetyl cysteinDissolve 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-constrictorExample• 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

inhibitionAction 

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-histaminic1. 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)Drug

s

Example Action PotencySodium cromoglycate

(opticrome)Mast cell stabilizer 1

Lodoxamide (Alomide)Mast cell stabilizer +

Eosionophil suppressorx 2500

Mast cell stabilizerUsed as a prophylaxis NOT as a TTT, because:1. They does NOT interfere with binding of antigen to previously sensitized cells2. NO anti-histaminic action

Drugs

EcosanoidsEico = 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-SAIDClasses 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)Drug

s

العنوان عارف مش لسه• SAID• Prostaglandin analoguesUse: TTT of open angle glaucomaN.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) Drug

s

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.

Routes of drug administration• 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

Potency

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 actionIt enters cell membrane without need of receptors.

Anti-inflammatory & immune-suppressive Anti-allergic : allergic type I hyper-sensitivity

DrugsAnti-

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 Drug

s

N.B. It causes neutrophilia!! but inhibits neutrophil migration

N.B. lymphocytes ( T cells > B cells )

Drugs

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 ابقىSide 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 therapy42 % have IOP > 20 mmHg6 % have IOP > 31 mmHg

Side effects of topical steroid1. Mild ptosis2. V.C. of conjunctival blood vessels 3. Ocular discomfort4. Corneal thickening5. Inhibition of corneal epithelial healing & neovascularization6. 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-fluorouracil (5FU)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

5-fluorouracil (5FU)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.

MnemonicsMitomycin C 5 FU

Any phase(Maximally S or G

phase)

S phase Stage of cell cycle affection

Mitomycin 100 times potent PotencyPermanent 4-6 weeks

(5 weeks)Effect on fibroblast

NO Yes Epithelial 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)

MethotrexateAzathioprine

(imurane)Alkylating agents

(Create cross linking between DNA strands inhibition of mRNA transcription inhibition of DNA synthesis)

Chlorambucil (Leukran)

Cyclophosphamide (Cytoxan)

Cyto-static   SteroidImmuno-

modulator  Cyclosporin

Others Colchicine(Inhibition of leucocyte migration)Use: Prevention of Behcet's recurrence

 

Oncolytic agents  

Uses1. Prevention of allo-graft rejection2. Auto-immune diseases3. Chronic allergy4. Endogenous uveitis

Drugs

Cyto-toxic drugs

Drugs

  Action Side effectsChlorambucil   Sterility

B.M. suppressionAzathioprine(Purine analogue)

Inhibits purine synthesis blocks DNA & RNA synthesis

B.M. suppressionGIT 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. suppressionGIT upsetTeratogenic

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 tumorSterilityB.M. suppression

Others

Drugs

  Action Side effectsCorticosteroid

Block transcription of cytokine genes(IL1,2,3,5 – TNFα – interferon

OsteoporosisHypertensionGlucose intolerance

Cyclosporin Inhibits IL2 production inhibits lymphocytes proliferation & activation

OF systemic use ONLYNephrotoxicHypertensionGlucose intoleranceHyperlipidemiaHirsutismGingival hyperplasiaPeripheral neuropathyHepatotoxicityHyperuricemia

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 Drug

s

== 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 anestheticsDrugs 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

يخترقPenetrate myelin

يخدر

Local anesthetics• So, action depends on pH:

Drugs

In alkaline pH In acidic pHexample NaHCO3 Inflamed woundResult 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 penetration2. 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. access2. Monitor: heart rate – O2 saturation

Local anesthesia should NEVER be administered systemically

Infiltrative anesthesia

Drugs

  Peri-bulbar Retrobulbar Site Outside muscle cone Inside muscle coneAdvantage 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-linkedOnset 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-estraseLiver: 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 toxicityCocaine > 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- bleeding2* Mixture alter pH (as epinephrine is acidic) amount of non-ionized form penetration3* Destroyed by heat

Drugs

Drugs

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

Anti-glaucomatousDrugs

Drugs

Anti-glaucomatous drugs1. Cholinergic drugs (parasympatho-mimetics)2. Adrenergic drugs ( sympatho-mimetics)3. Adrenergic drugs (Beta blockers)4. Osmotic agents5. Prostaglandins6. 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 effectsLocal- Allergy- Lid retraction- Conjunctival blanching- MydriasisSystemic• Dry eye & mouth• Headache• May exacerbate IHD• hypOtension ! Drug

s

ApraclonidineContraindicated • Allergy• Patient is taking MAO & TCA (tri-cyclic anti-depressants)

Used cautiously in • ورضاعة حمل• Orthostatic hypOtension• Raynaud’s phenomena• Cardio vascular diseases• In combination with (BB – antihypertensive – digitalis)

Drugs

Brimonidine (aphagan)Side effectsLocal- 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 insufficiencyIn combination with (CNS depressants as alcohol, barbiturates, opiates …)

الديبرشن بيزود

Drugs

Adrenaline

Drugs

Contraindication Side effects Allergy

Rebound phenomena (VC → VD)

NOT used with contact lenses

Black 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 cautiously Tachycaria / arrythimaUsed cautiously hypertension

Hyperthyroidism والرضاعة والحملused cautiously

3. Beta blockersNon-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)

TimololNon-selective BB • Metabolized by liver• Relatively α1 antagonists (give additive response if used with

pilocarpine)

Drugs

Timolol is stronger than pilocarpine in lowering IOP

CartelolNon-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 الميزتينDrug

s

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

Drugs

Beta blockersSide effectsLocal: allergy +• SPK• Corneal anesthesia• Dry eye• Hypermia

Drugs

Beta blockersSystemic: 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 Drug

s

Heart

CNS

Lipid soluble BB cause bad dreams ˃ water soluble BB

As lipid soluble drugs pass blood brain barrier

Beta blockersSystemic:

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 blockersContraindicated • Cardiac patients• Asthmatic patients• Myasthenia gravisUsed cautiously in

ورضاعة حملHyperthyroidism ???? الثيرويد مع بنستخدمه واحنا ازاي

Drugs

Used cautiously with diabetic patients, WHY ?1.↓ Glycogenolysis & glauconeogenesis2.↓ 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 drugsIf 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 agentsOral I.V

Glycerol Mannitol 20% Iso-sorbid Urea

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 nerveF

Take care in renal

failure

Mannitol side effectsDraw 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 glycerolأوي مسكر

• Nausea – vomiting (so, mixed with lemon juice)

• Hyperglycemia• Hyperosmotic coma• DKA

Drugs

) برتقان ) مش ويشربه لموون عصير على باحطه

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

مشاكل .. بيع®مل لقوه بروستاجالندين عن عبارة الدوا كان زمانبندي بقينا

Prodrug which is activated by hydrolysis at cornea

30 % reduction in IOP

Side effects• LocalLashes: 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 pregnancyUsed Cautiously at: - Lactation- Intra-ocular inflammation !

Latanoprost

Drugs

Half life in eye Half 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 !! *Drug

s

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 proteins5 % unbounded 50% unionized → cell penetration 50% ionized → NO cell penetration

Drugs

WHY alkaline urine ?? as it ↑ urinary bicarbonate & ↓ urinary citrate

Carbonic anhydrase • Actions1. ↓ 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

Topical Systemic (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 7This 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• Duration: 24 hours

• Onset: 1 minute• Peak: 10 minutes• Duration: 4 hours

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

Methazolamide Dicholrphenamideزيه 1 X 2 or 1 X 3 Tablet 50 mg

3 hours 1 hour Onset

Use of systemic CAI: - Short term therapy with acute glaucoma

مصايبه عشان كتير بنستخدموش ما-

Drugs

Others: idiopathic intracranial HTNزبطهAdjunctive therapy for petit mal epilepsy

Side effects of acetazolamide1. In eye:- Transient myopia (d.t. C.B. odema → forward shift of iris & lens → shallow A.C.)

√- Dry eye2. 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)

TTTNa acetate 2 weeks

Systemic side effectsباقي - 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

oDose-related B.M suppression (Reversible if drug stopped)o Idiosyncrasy aplastic anemia (Not dose related) Drug

s

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 TTT1. Mono-therapy:

Why PG? [ Once – Low SE – Potent IOP ]If failed2. Combined therapy: ……………. (also consider systemic CAI)If failed3. Laser Drug

s

PG BBAlpha

agonist or CAI

(topical)

CombinationsDose Composition Combinatio

n1 X 2 Dorzolamide

TimololCosopt

1 X 2 Brimonidine Combigan

1 X 2 Pilocarpine Timpilo

1 X 1 Latanoprost Xalacom

1 X 1 Travoprost Puotrav

1 X 1 Bimatoprost Ganfort

Drugs

Special cases in glaucoma TTTGlaucoma 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 pregnancyAll drugs affect pregnancy

1st line of TTT is laser trabeculoplasty (Selective is better than argon)

Although the lower potential of success ! Drugs

Autonomic nervous systemSympathetic

Drugs

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