ocular pharmacology
TRANSCRIPT
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Ocular pharmacology
Dr. Ahmed Omara
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Contents• Pharmaco-kinetics• Pharmaco-dynamics• Routes of drug administration• Preservatives• Drugs
Pharmacology
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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
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Pharmacokinetic
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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
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1. AbsorptionDepends on:1. Diffusion2. Carrier molecule = facilitated diffusion: NOT against concentration gradient3. Pinocytosis4. Active: against concentration gradient
Pharmacokinetic
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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
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Pharmacokinetic
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Fick’s law of diffusion
Pharmacokinetic
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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
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Examples for prodrugs• Dipivefrin (propine) : Pro-drug of epinephrine (Penetration x
17) • Nepafenac (Nevanac): Pro-drug of amfenac
Pharmacokinetic
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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
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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
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Distribution to eye is limited by blood ocular barriers
Pharmacokinetic
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Pharmacokinetic
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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
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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
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Drugs acting on microsomal enzymes
Drugs acting on microsomal enzymes+ -
Rifampicin IsoniazideGriseofulvin Chloramphenicol
MetronidazolBarbiturate
PhenothiazinePhenytoin
Nicotine Warfarine CO Pharmacokin
etic
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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
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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.)
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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
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Pharmaco-dynamics = Drug handling by the body
Study of biochemical & physiological effects of drugs & their mechanism of action
Pharmaco-dynamic
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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
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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
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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
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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
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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
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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
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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 %
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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
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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
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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
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OintmentHydro-carbon + oil + lanolin + polymer (poly-vinyl alcohol or
methyl-cellulose)- Side effects:Blurring of visionContact dermatitis (d.t. preservative)
Routes
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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
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Collagen shield- Antibiotics- Dexamethason- Prednisolon- Cyclosporine A
Routes
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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…
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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
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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)!
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للفهم محاولة
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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
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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
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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
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Note: NLD & drugsNLD: Make drugs to be absorbed systemic
N.B. To systemic absorption: close the punctum for 5 minutes after drops administration
Routes
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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
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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
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Notes: preservatives• ChlorbutolSide effect: O2 utilization by cornea epithelium desquamation
• Thiomersal/Phenyl-mercuric nitrate Side effect:- Allergy- Deposits الزئبق
preservatives
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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
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Reconstituting tear film2. Mucolytics: e.g. acetyl cysteinDissolve mucous thread problem in keratoconjunctivitis sicca
Drugs
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Anti-allergic drugs• Anti-histaminic• Vaso-constrictor• Mast cell stabilizer
Drugs
Mast cell stabilizer
Vaso-constrictor
Anti-histaminic
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1. Vaso-constrictorExample• Naphzoline (Naphcon A)• Pheniramine maleate
N.B. Vaso-constrictors can cause rebound redness! (on chronic use)
Drugs
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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
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Topical anti-histaminic1. Levo-carb-astine (livostine)2. Emed-astine (Emadine)
Drugs
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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
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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
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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
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EcosanoidsEico = 20 [as their origin is arachidonic acid (which is 20-carbon fatty acid)]
Formation:
Drugs
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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
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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
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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
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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
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Glauco-corticoids
Drugs
Plasma cortisol:
- Maximal at 6-8 A.M
- Lowest at mid-night.
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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
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Potency
Drugs
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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
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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
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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 )
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Drugs
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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)
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Uses of cortison• Lid inflammation• Conjunctival inflammation• Corneal inflammation• Hyphema• Iridocyclitis• Endophthalmitis• Macular odema• C.N.V
Drugs
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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
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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
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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
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Side effects of peri-ocular steroid
Locally:• Glaucoma• Cataract• Proptosis• Retinal & choroidal vessels occlusion
Systemic:• Cushing's syndrome• Systemic hypertension
Drugs
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التصنيف عارف مش
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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.
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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
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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
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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.
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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.
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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
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Immuno-suppressive drugs
Drugs
Drugs controlling immune response (especially T lymphocyte)
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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
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Uses1. Prevention of allo-graft rejection2. Auto-immune diseases3. Chronic allergy4. Endogenous uveitis
Drugs
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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
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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
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== 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
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== 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
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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
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Local anesthetics• * N.B. Local anesthetic has 2 portions
Drugs
Non-ionized = Non-cationic = Lipophilic
Ionized = Cationic = Hydrophilic
يخترقPenetrate myelin
يخدر
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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)
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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
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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)
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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
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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
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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
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Drugs
Benoxinate has some anti-microbial effects e.g. against staphylococci, pseudomonas & candida.
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Anti-glaucomatousDrugs
Drugs
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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
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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
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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
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Side effects of pilocarpine• Systemic: RARE• Sweating• Nausea • Vomiting• Abdominal colic• Bradycardia• Bronchospasm
Drugs
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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
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2. Sympathomimetics Non-selective• Adrenaline• Dipivefrin (propine)Selective• Clonidine [Obsolete: pass blood brain barrier →
hypOtension]• Apraclonidine (α agonist) • Brimonidine (α2 agonist)
Drugs
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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
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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
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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
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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
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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
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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)
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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
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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
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Levobunolol (Betagan)Non-selective BB • 30% ↓ IOP• Action: 24 hours (but taken also 1 X 2)
Drugs
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Beta blockersSide effectsLocal: allergy +• SPK• Corneal anesthesia• Dry eye• Hypermia
Drugs
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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
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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)
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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
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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
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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
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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 %
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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
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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
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Urea I.V.
• Distributed allover the body (high solubility) [ EC & IC]• Excreted by kidney (in urine)
Drugs
NOT commonly used ??Extravasation → tissue necrosis
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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 !
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Side effects of glycerolأوي مسكر
• Nausea – vomiting (so, mixed with lemon juice)
• Hyperglycemia• Hyperosmotic coma• DKA
Drugs
) برتقان ) مش ويشربه لموون عصير على باحطه
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Iso-sorbid• Dose: 1gm/kg or 2ml/kg (orally) [ Minty taste]• Metabolically inert (NOT metabloized)• May be given to diabetics without insulin cover
Drugs
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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
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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 !
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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
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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
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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
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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
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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
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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
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Drugs
Methazolamide Dicholrphenamideزيه 1 X 2 or 1 X 3 Tablet 50 mg
3 hours 1 hour Onset
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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
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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
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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 !!
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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
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Contraindicated in• رضاعة حمل• HypOkalemia – HypOnatremia• Renal stones
Drugs
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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)
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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)
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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
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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
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Autonomic nervous systemSympathetic
Drugs
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Routes of drug administration• Add your first bullet point here
Drugs
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Drugs
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Title and Content Layout with Chart
Category 1 Category 2 Category 3 Category 40
1
2
3
4
5
6
Series 1Series 2Series 3
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Two Content Layout with Table•First bullet point here•Second bullet point here•Third bullet point here
Group 1 Group 2
Class 1 82 95
Class 2 76 88
Class 3 84 90
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Two Content Layout with SmartArt
•First bullet point here•Second bullet point here•Third bullet point here
Group A
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